ElShamah - Reason & Science: Defending ID and the Christian Worldview
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ElShamah - Reason & Science: Defending ID and the Christian Worldview

Welcome to my library—a curated collection of research and original arguments exploring why I believe Christianity, creationism, and Intelligent Design offer the most compelling explanations for our origins. Otangelo Grasso


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Biochemical fine-tuning - essential for life

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Biochemical fine-tuning - essential for life

https://reasonandscience.catsboard.com/t2591-biochemical-fine-tuning-essential-for-life

M.Eberlin (2019): DNA’s Four Bases Another crucial question: Why did life “choose” the very specific ATGC quartet of N bases? Another indication of the planning involved in the DNA chemical architecture arises from the choice of a four-character alphabet used for coding units three characters long. Why not more alphabetic characters, or longer units? Some of my fellow scientists are working on precisely such genetic Frankensteins. It’s fascinating work. But DNA should be as economical as possible, and for DNA to last, it had to be highly stable chemically. And these four bases are exactly what are needed. They are highly stable and can bind to ribose via strong covalent N-O bonds that are very secure. Each base of this “Fantastic Four” can establish perfect matchings with precise molecular recognition through supramolecular H-bonds. The members of the G≡C pair align precisely to establish three strong, supramolecular hydrogen bonds. The A=T pair align to form two hydrogen bonds. A and G do not work, and neither do C and T, or C and A, or G and T. Only G≡C and A=T work. But why don’t we see G≡G, C≡C, A=A or T=T pairings? After all, such pairs could also form two or three hydrogen bonds. The reason is that the 25 Å space between the two strands of the double helix cannot accommodate pairing between the two large (bicyclic) bases A and G, and the two small (monocyclic) bases T and C would be too far apart to form hydrogen bonds.9 A stable double helix formed by the perfect phosphate-ribose polymeric wire, with proper internal space in which to accommodate either A=T or G≡C couplings with either two or three H-bonds is necessary to code for life. And fortunately, that is precisely what we have.


Graham Cairns-Smith: Fine-tuning in living systems: early evolution and the unity of biochemistry   11 November 2003
We return to questions of fine-tuning, accuracy, and specificity. Any competent organic synthesis hinges on such things. In the laboratory, the right materials must be taken from the right bottles and mixed and treated in an appropriate sequence of operations. In the living cell, there must be teams of enzymes with specificity built into them. A protein enzyme is a particularly well-tuned device. It is made to fit beautifully the transition state of the reaction it has to catalyze. Something must have performed the fine-tuning necessary to allow such sophisticated molecules as nucleotides to be cleanly and consistently made in the first place.
https://www.cambridge.org/core/journals/international-journal-of-astrobiology/article/abs/finetuning-in-living-systems-early-evolution-and-the-unity-of-biochemistry/193313763244F9E6D085A3F062110389

Yitzhak Tor: On the Origin of the Canonical Nucleobases: An Assessment of Selection Pressures across Chemical and Early Biological Evolution 2013 Jun; 5
How did nature “decide” upon these specific heterocycles? Evidence suggests that many types of heterocycles could have been present on the early Earth. It is therefore likely that the contemporary composition of nucleobases is a result of multiple selection pressures that operated during early chemical and biological evolution. The persistence of the fittest heterocycles in the prebiotic environment towards, for example, hydrolytic and photochemical assaults, may have given some nucleobases a selective advantage for incorporation into the first informational polymers.

The prebiotic formation of polymeric nucleic acids employing the native bases remains, however, a challenging problem to reconcile. Two such selection pressures may have been related to genetic fidelity and duplex stability. Considering these possible selection criteria, the native bases along with other related heterocycles seem to exhibit a certain level of fitness. We end by discussing the strength of the N-glycosidic bond as a potential fitness parameter in the early DNA world, which may have played a part in the refinement of the alphabetic bases. Even minute structural changes can have substantial consequences, impacting the intermolecular, intramolecular and macromolecular “chemical physiology” of nucleic acids 4

Libretext: In the context of DNA, hydrogen bonding is what makes DNA extremely stable and therefore well suited as a long-term storage medium for genetic information. 5

Amazing fine-tuning to get the right hydrogen bond strengths for Watson–Crick base-pairing

The hydrogen bond strength between nucleotides in DNA base pairing is finely tuned and plays a crucial role in the stability and specificity of DNA double helix formation. In DNA, the base pairs consist of adenine (A) with thymine (T) and guanine (G) with cytosine (C). The base pairing is driven by hydrogen bonds between complementary nucleotides: A forms two hydrogen bonds with T, and G forms three hydrogen bonds with C. These hydrogen bonds are relatively weak individually but collectively provide the stability needed for the DNA structure. The strength of hydrogen bonds in DNA base pairing is carefully balanced to ensure the stability of the double helix while allowing for selective base pairing. The hydrogen bonds must be strong enough to maintain the integrity of the DNA molecule but not so strong that they become difficult to break during processes such as DNA replication and transcription. The specificity of DNA base pairing is determined by the complementary shapes and hydrogen bonding patterns between the nucleotide bases. Adenine forms hydrogen bonds with thymine specifically, and guanine with cytosine specifically, due to the specific geometry and arrangement of functional groups on the bases. This precise tuning of hydrogen bond strength and complementary base pairing is essential for the accurate replication and transmission of genetic information in DNA. Any significant deviation in hydrogen bond strength or base pairing specificity could result in errors in DNA replication and potentially disrupt the functioning of genetic processes.  

The right bond strength in DNA base pairing depends not only on the hydrogen bonds themselves but also on the proper tautomer configuration of the nucleotide bases involved. Tautomeric forms of nucleotide bases refer to different arrangements of atoms within the base structure, which can lead to variations in hydrogen bonding patterns. Tautomerism involves the migration of a hydrogen atom and the rearrangement of double bonds within the molecule. The different tautomeric forms of nucleotide bases can exhibit different hydrogen bonding capabilities. In the context of DNA base pairing, the correct tautomeric form of each nucleotide base is essential for achieving stable and specific hydrogen bonding. The hydrogen bonds between A-T and G-C pairs rely on the proper tautomeric configurations of the bases to form the appropriate number of hydrogen bonds and maintain the structural integrity of the DNA molecule. For example, in the case of adenine, it can exist in two tautomeric forms known as amino and imino. Only the amino tautomer of adenine can form two hydrogen bonds with thymine, allowing for the stable A-T base pair. Similarly, guanine can exist in two tautomeric forms, keto and enol, and only the keto form can form three hydrogen bonds with cytosine, leading to the stable G-C base pair. The proper tautomeric configurations and hydrogen bonding patterns between nucleotide bases are crucial for the specificity and stability of DNA base pairing, which, in turn, is fundamental for the accurate replication and transmission of genetic information.

There are many possible analog atom compositions and structural variations for nucleotide bases, including different ring structures. The fundamental components of nucleotide bases are heterocyclic aromatic rings, which can have various compositions and arrangements of atoms. For example, purine bases, such as adenine and guanine, have a double-ring structure, while pyrimidine bases, such as cytosine, thymine, and uracil, have a single-ring structure. These bases can have different substituents, functional groups, or modifications, leading to a wide range of possible variations. In addition, analogs and derivatives of nucleotide bases can be synthesized or occur naturally, further expanding the potential variations. These analogs can have modified atoms, altered functional groups, or different positions of substituents within the base structure. Considering all the possible combinations of atoms, functional groups, and modifications, the number of potential nucleotide base compositions and structures can indeed be considered vast, if not infinite. However, it is important to note that within biological systems, only specific nucleotide bases are found in DNA and RNA, as they provide the necessary chemical properties and base pairing specificity for genetic information storage and transmission.

The selection of the right hydrogen bond strengths, as well as other critical aspects, play a significant role in configuring functional building blocks of life. Several factors need to be considered for the right selection to occur:

Tautomers and Isomers: Tautomers are structural isomers that exist in dynamic equilibrium, differing in the placement of protons and double bonds. Isomers, on the other hand, are molecules with the same molecular formula but different structural arrangements. The selection of the appropriate tautomers and isomers would be crucial as it affects the chemical reactivity, stability, and functional properties of the molecules involved.

Atom Analogues: The selection of the right atom analogues is important in the context of prebiotic chemistry. For example, in organic chemistry, carbon is the primary element, as it possesses unique bonding capabilities. However, other elements like nitrogen, oxygen, and phosphorus also play essential roles in the formation of organic molecules and biochemical processes.

Number of Atoms and Ring Structures: The number of atoms and the arrangement of these atoms within a molecule can significantly influence its stability and reactivity. Moreover, the formation of ring structures can introduce additional complexity and functional diversity. The selection of the appropriate number of atoms and the arrangement of ring structures would contribute to the suitability and functionality of the building blocks.

Overall Arrangement: The overall arrangement or spatial configuration of molecules is crucial for their interactions and functional properties. Stereochemistry, which deals with the three-dimensional arrangement of atoms, plays a vital role in determining the biological activity and compatibility of molecules.

Premise 1: The selection of the right tautomers, isomers, atom analogs, number of atoms, ring structures, and the overall arrangement is crucial for configuring functional building blocks of life.
Premise 2: Achieving the precise combination of these factors, such as the right hydrogen bond strengths and Watson-Crick base pairing, requires an intricate level of specificity and fine-tuning.
Conclusion: An intelligent designer is the best explanation for functional nucleobases that provide the right hydrogen bond strengths and Watson-Crick base pairing.

Explanation: The selection of the appropriate tautomers, isomers, atom analogs, number of atoms, ring structures, and the overall arrangement is essential for the formation of functional building blocks of life. Achieving the necessary level of precision and specificity in these factors, especially when considering the right hydrogen bond strengths and Watson-Crick base pairing, points to the involvement of an intelligent designer. The complexity and interdependence of these factors suggest that a random, naturalistic process alone would have difficulty accounting for the precise combination required for functional nucleobases. The intricate design and fine-tuning necessary to achieve the desired outcomes, which are crucial for the functioning of genetic information, strongly support the idea of an intelligent designer guiding the process. While naturalistic explanations can account for some aspects of chemical interactions and molecular properties, the specific configuration required for functional nucleobases and their ability to exhibit the right hydrogen bond strengths and Watson-Crick base pairing provides a more compelling explanation for the involvement of an intelligent designer.

Premise 1: Natural selection relies on the variation and differential reproductive success of individuals within a population.
Premise 2: The prebiotic Earth lacked the presence of life forms, including self-replicating organisms or cells.
Conclusion: The absence of natural selection on the prebiotic Earth makes naturalistic explanations for the selection of the right building blocks of life basically impossible.

Explanation: Natural selection operates through the mechanism of variation in traits within a population and the subsequent reproductive success of individuals with advantageous traits. However, in the absence of life on the prebiotic Earth, there were no organisms or cells with traits that could undergo selection. Without the presence of replicating entities, there would be no variation or differential reproductive success to drive natural selection.
Therefore, it becomes challenging to explain the selection of the right building blocks of life through naturalistic means alone on the prebiotic Earth. Other mechanisms, such as chemical reactions, environmental factors, or random chance, are also not a plausible explanation, and could not have played a role in the formation and selection of the building blocks of life.

Creationsafari (2004) DNA: as good as it gets?  Benner spent some time discussing how perfect DNA and RNA are for information storage.  The upshot: don’t expect to find non-DNA-based life elsewhere.  Alien life might have more than 4 base pairs in its genetic code, but the physical chemistry of DNA and RNA are hard to beat.  Part of the reason is that the electrochemical charges on the backbone keep the molecule rigid so it doesn’t fold up on itself, and keep the base pairs facing each other.  The entire molecule maximizes the potential for hydrogen bonding, which is counter-intuitive since it would seem to a chemist that the worst environment to exploit hydrogen bonding would be in water.  Yet DNA twists into its double helix in water just fine, keeping its base pairs optimized for hydrogen bonds, because of the particular structures of its sugars, phosphates, and nucleotides.  The oft-touted substitute named PNA falls apart with more than 20 bases.  Other proposed alternatives have their own serious failings. 5

Assignmentpoint: The existence of Watson–Crick base-pairing in DNA and RNA is crucially dependent on the position of the chemical equilibria between tautomeric forms of the nucleobases.  Tautomers are structural isomers (constitutional isomers) of chemical compounds that readily interconvert. The chemical reaction interconverting the two is called tautomerization. This conversion commonly results from the relocation of a hydrogen atom within the compound. Tautomerism is for example relevant to the behavior of amino acids and nucleic acids, two of the fundamental building blocks of life. 3

Bogdan I. Fedeles: Structural Insights Into Tautomeric Dynamics in Nucleic Acids and in Antiviral Nucleoside Analogs 25 January 2022
For nucleobases, tautomers refer to structural isomers ( In chemistry, a structural isomer of a compound is another compound whose molecule has the same number of atoms of each element, but with logically distinct bonds between them.) that differ from one another by the position of protons. By altering the position of protons on nucleobases, many of which play critical roles in hydrogen bonding and base-pairing interactions, tautomerism has profound effects on the biochemical processes involving nucleic acids.

Pavel Hobza: Structure, Energetics, and Dynamics of the Nucleic Acid Base Pairs: Nonempirical Ab Initio Calculations June 29, 1999
There are nucleobases such as uracil or thymine for which there is a very large energy gap between the major form and minor tautomers. For some other bases (guanine, cytosine) there are several energetically acceptable tautomers. However, the major tautomer forms are still the only ones that appear in nucleic acids under normal circumstances. Many rare tautomers are destabilized by solvent effects, or they do not lead to a pairing compatible with the nucleic acids architecture. 2

Barrow, FITNESS OF THE COSMOS FOR LIFE,  Biochemistry and Fine-Tuning, page 154
These equilibria in both purines and pyrimidines lie sharply on the side of amide- and imide-forms containing the (exocyclic) oxygen atoms in the form of carbonyl groups (C=O) and (exocyclic) nitrogen in the form of amino groups (NH2). The positions of these equilibria in a given environment are an intrinsic property of these molecules, determined by their physico-chemical parameters (and thus, ultimately, by the fundamental physical constants of this universe). The chemist masters the Herculean task of grasping and classifying the boundless diversity of the constitution of organic molecules by using the concept of the “chemical bond.” He pragmatically deals with the differences in the thermodynamic stability of molecules by using individual energy parameters, which he empirically assigns to the various types of bonds in such a way that he can simply add up the number and kind of bonds present in the chemical formula of a molecule and use their associated average bond energies to estimate the relative energy content of essentially any given organic molecule. As it happens, the average bond energy of a carbon-oxygen double bond is about 30 kcal per mol higher than that of a carbon–carbon or carbon–nitrogen double bond, a difference that reflects the fact that ketones normally exist as ketones and not as their enol-tautomers. If (in the sense of a “counterfactual variation”) the difference between the average bond energy of a carbon–oxygen double bond and that of a carbon–carbon and carbon–nitrogen double bond were smaller by a few kcal per mol, then the nucleobases guanine, cytosine, and thymine would exist as “enols” and not as “ketones,” and Watson–Crick base-pairing would not exist – nor would the kind of life we know. It looks as though this is providing a glimpse of what might appear (to those inclined) as biochemical fine-tuning of life. However, I agree with Paul Davies’ comment at the workshop: in order for the proposed change of the bond energy of a carbon–oxygen double bond to be a proper counterfactual variation of a physicochemical parameter, we concomitantly would have to change the bond energies of all other bonds occurring in the chemical formulae of the nucleobases in such a way that we would remain internally consistent within the frame of molecular physics. To do this in a theory-based way is not feasible because the average energies assigned to (isolated) chemical bonds are empirical parameters that have no direct equivalents in quantum-mechanical models of organic molecules. Without the possibility of calculating bond energies from first principles, average bond energies cannot be meaningfully used as a parameter for counterfactual variation.

On the other hand, calculating the position of tautomeric equilibria in nucleobases is certainly within the grasp of contemporary quantum chemistry, and semi-empirical physico-chemical parameters on which the positions of these equilibria might most sensitively depend could presumably be identified. Whether in this special case it would be feasible and conceptually proper to attempt an internally consistent variation of Physico-chemical parameters followed by calculation of associated properties for resulting virtual nucleobases is a question to be answered by a quantum chemist rather than an experimentalist. It nevertheless would seem that Watson–Crick pairing is a promising target (for those so inclined) in a theory-consistent search for a biochemical example of fine-tuning of chemical matter toward life. It represents an example of a question referring to existence that might be reduced to a question of the position of chemical equilibrium between tautomers. Irrespective of the outcome of such a search, the cascade of coincidences embodied in nature’s canonical nucleobases will remain, from a chemical point of view, an extraordinary case of evolutionary contingency on the molecular level (even to those unconcerned about the question of a biocentric universe). The generational simplicity of these bases when compared with their relative constitutional complexity,  their capacity to communicate with one another in specific pairs through hydrogen bonding within oligonucleotides, and, finally, the role they were to take over at the dawn of life and to play at the heart of biology ever since is extraordinary. I have little doubt that Henderson – could he have known it – would have added these coincidences to his list of facts that were, to him, convincing evidence for the environment’s fitness to life.
 Let us then assume, for the sake of argument, that the equilibria between the tautomers of the nucleobases prevented Watson–Crick base-pairing of the kind we know. Would there be an alternative higher form of life? If we were to answer in the affirmative – aware of the immense diversity of the structures and properties of organic molecules and conscious of the creative powers of evolution – could we have any idea of what such a life form might look like, chemically? The helplessness that overwhelms us as chemists in being confronted with such a question can give rise to two different reactions. Some of us would seek comfort in declaring that such questions do not belong to science, and others would simply be painfully reminded of how little we really know and comprehend of the potential of chemical matter to become and to be alive. Our insight into the creativity of biological evolution on the molecular level is far too narrow for us to judge by biochemical reasoning what would have happened to the origin and the evolution of life if they had had to occur and operate in a world of (slightly) different physico-chemical parameters. 

I shall return to this point below. Statements about fine-tuning toward life in cosmology referring to criteria such as the potential of a universe to form heavy elements and planets are in a category fundamentally different from statements about fine-tuning of physico-chemical parameters toward life at the level of biochemistry. Whatever biological phenomena appear fine-tuned can be interpreted in principle as the result of life having fine-tuned itself to the properties of matter through natural selection. Indeed, to interpret in this way what we observe in the living world is mainstream thinking within contemporary biology and biological chemistry. 

My comment: It strikes me how un-imaginative these folks are. They cannot imagine anything else besides NATURAL SELECTION. So the hero on the block strikes again. The multi-versatile mechanism propagated by Darwin explains and solves practically any issue and arising question of origins. Can't explain a phenomenon in question? natural selection must be the hero on the block. It did it.....  huh...

Thus, life science and cosmology are in very different positions when it comes to the question of how to interpret, or even identify, data that point to fine-tuning. To return to our example: in biology, the existence of a central feature such as Watson–Crick base-pairing may be seen as an achievement of life’s evolutionary exploration of, and adaption to, the chemical potential of matter on planet earth. In cosmology, there is no corresponding way to interpret the formation of, let us say, a planet, and proposals of “evolutionary” universe-selection imposed on multiverse models would fall short of creating a correspondence.

Nassim Beiranvand: Hydrogen Bonding in Natural and Unnatural Base Pairs—A Local Vibrational Mode Study  2021 Apr; 26
In summary, our study clearly reveals that not only the intermolecular hydrogen bond strength but also the combination of classical and non-classical hydrogen bonds play a significant role in natural base pairs, which should be copied in the design of new promising unnatural base pair candidates. Our local mode analysis, presented and tested in this work provides the bioengineering community with an efficient design tool to assess and predict the type and strength of hydrogen bonding in artificial base pairs.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8071019/

C.Ronald Geyer: Nucleobase Pairing in Expanded Watson-Crick-like Genetic Information Systems  December 2003
Within the constraints of the Watson-Crick rules, six canonical pairing schemes exploiting three hydrogen bonds can be conceived using carbon/nitrogen ring systems that are isosteric (  molecules or ions with similar shape and often electronic properties ) to natural purines or pyrimidines. Even within the six pairing schemes, the number of possibilities is enormous. Analogous nucleobase pairs can be joined by fewer than three H-bonds by omitting specific H-bonding functionality. This is the case with the natural A-T pair. Further, the addition or removal of heteroatoms can change the physical properties of the heterocycles (e.g., their acid-base properties), substituents can be added, and the nature of the nucleobase-sugar linkage can be changed.

Song Mao: Base pairing, structural and functional insights into N4 -methylcytidine (m4C) and N4 ,N4 -dimethylcytidine (m4 2C) modified RNA 17 September 2020
RNA chemical modifications have been increasingly recognized as one of nature’s general strategies to define, diversify, and regulate RNA structures and functions in numerous biological processes. To date, over 160 post-transcriptional modifications have been identified in all types of RNAs in the three domains of life. Many of these modifications have been demonstrated to play critical roles in both normal and diseased cellular functions and processes such as development, circadian rhythms, embryonic stem cell differentiation, meiotic progression, temperature adaptation, stress response, tumorigenesis, etc. Similar to DNA and protein epigenetic markers, these RNA modifications, also termed as ‘epitranscriptome’, can be dynamically and reversibly regulated by specific reader, writer, and eraser enzymes, representing a new layer of gene regulation.

My comment: For the well-intended above has clear teleological implications. Developing strategies to regulate, or to modify things in order to achieve specific functions that play critical roles in higher-order functions of a system has always been associated with conscious, goal-orientated action by intelligence. Furthermore, in order to have a communication system based on reading, writing, and erasing ( information that is not useful anymore) requires the set-up of a language understood by all parties, with a convention of meaning of words. Such things depend always on a goal-oriented set-up by intelligence.  

The just right ribose structure
Conceive (through chemical reasoning) potentially natural alternatives to the structure of RNA; synthesize such alternatives by chemical methods; compare them with RNA with respect to those chemical properties that are fundamental to its biological function. Fortunately for this special case of the nucleic acids, it is not at all problematic to decide what the most important of these properties has to be: it must be the capability to undergo informational Watson–Crick base-pairing. The relevance of the perspective created in such a project will strongly depend on the specific choice of the alternatives’ chemical structures. The quest is to focus on systems deemed to be potentially natural in the sense that they could have formed, according to chemical reasoning, by the very same type of chemistry that (under unknown circumstances) must have been operating on earth (or elsewhere) at the time when and at the place where the structure type of RNA was born. Candidates that lend themselves to this choice are oligonucleotide systems, the structures of which are derivable from (CH2O)n sugars (n = 4, 5, 6) by the type of chemistry that allows the structure of natural RNA to be derived from the C5-sugar ribose. This approach is based on the supposition that RNA structure originated through a process that was combinatorial in nature with respect to the assembly and functional selection of an informational system within the domain of sugar-based oligonucleotides. In a way, the investigation is an attempt to mimic the selection filter of such a natural process by chemical means, irrespective of whether RNA first appeared in an abiotic or abiotic environment. In retrospect, the results of systematic experimental investigations carried out along these lines justify the effort.

It is found that hexopyranosyl analogs of RNA (with backbones containing six carbons per sugar unit instead of five carbons and six-membered pyranose rings instead of five-membered furanose rings) do not possess the capability of efficient informational Watson–Crick base-pairing. Therefore, these systems could not have acted as functional competitors of RNA in nature’s choiceof a genetic system, even though these six-carbon alternatives of RNA should have had a comparable chance of being formed under the conditions that formed RNA. 

My comment:  Nature does not make choices. Only intelligent agents with intent, will, and foresight do. The authors cannot resort to natural selection either, since at this stage, in the history of life, there was nothing to be selected.

The reason for their failure revealed itself in chemical model studies: six-carbon-six-membered-ring sugars are found to be too bulky to adapt to the steric requirements of Watson–Crick base-pairing within oligonucleotide duplexes. In sharp contrast, an entire family of nucleic acid alternatives in which each member comprises repeating units of one of the four possible five-carbon sugars (ribose being one of them) turned out to be highly efficient informational base-pairing systems. 
https://3lib.net/book/449297/8913bb

Guillermo Gonzalez, Jay W. Richards: The Privileged Planet: How Our Place in the Cosmos Is Designed for Discovery 2004 page 387
Arguably the most impressive cluster of fine-tuning occurs at the level of chemistry. In fact, chemistry appears to be “overdetermined” in the sense that there are not enough free physical parameters to determine the many chemical processes that must be just so. Max Tegmark notes, “Since all of chemistry is essentially determined by only two free parameters, alpha and beta [electromagnetic force constant and electron-to-proton mass ratio], it might thus appear as though there is a solution to an overdetermined problem with more equations (inequalities) than unknowns. This could be taken as support for a religion-based category 2 TOE [Theory Of Everything], with the argument that it would be unlikely in all other TOEs” (Tegmark, 15). Tegmark artificially categorizes TOEs into type 1, “The physical world is completely mathematical,” and type 2 “The physical world is not completely mathematical.” The second category he considers as motivated by religious belief.
https://3lib.net/book/5102561/45e43d

M.Eberlin Foresight (2019): DNA’s Four Bases Another crucial question: Why did life “choose” the very specific ATGC quartet of N bases? Another indication of the planning involved in the DNA chemical architecture arises from the choice of a four-character alphabet used for coding units three characters long. Why not more alphabetic characters, or longer units? Some of my fellow scientists are working on precisely such genetic Frankensteins. It’s fascinating work. But DNA should be as economical as possible, and for DNA to last, it had to be highly stable chemically. And these four bases are exactly what are needed. They are highly stable and can bind to ribose via strong covalent N-O bonds that are very secure. Each base of this “Fantastic Four” can establish perfect matchings with precise molecular recognition through supramolecular H-bonds. The members of the G≡C pair align precisely to establish three strong, supramolecular hydrogen bonds. The A=T pair align to form two hydrogen bonds. A and G do not work, and neither do C and T, or C and A, or G and T. Only G≡C,  and A=T work. But why don’t we see G≡G, C≡C, A=A, or T=T pairings? After all, such pairs could also form two or three hydrogen bonds. The reason is that the 25 Å space between the two strands of the double helix cannot accommodate pairing between the two large (bicyclic) bases A and G, and the two small (monocyclic) bases T and C would be too far apart to form hydrogen bonds.9 A stable double helix formed by the perfect phosphate-ribose polymeric wire, with proper internal space in which to accommodate either A=T or G≡C couplings with either two or three H-bonds is necessary to code for life. And fortunately, that is precisely what we have.








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https://libgen.lc/ads.php?md5=93BD1E56297FD8E9830AA31A3F06D70A

Electromagnetic Force Coupling Constant This coupling constant is also called the "fine structure constant" The strength of the electromagnetic force can be related to the force between two electrons given by Coulomb's law.
http://hyperphysics.phy-astr.gsu.edu/hbase/Forces/couple.html

Gabriel Popkin A More Finely Tuned Universe February 20, 2015
The scientists also varied the fine structure constant, which accounts for the strength of the electromagnetic force between charged particles. The strong force must overcome the electromagnetic force to bind protons and neutrons into stable nuclei that make up the familiar chemical elements: helium, carbon, oxygen and all the rest. The values of the average quark mass and the fine structure constant together also form a deep mystery. While the universe's matter is almost entirely hydrogen and helium, humans and other life forms on Earth are, by weight, mostly oxygen and carbon. All of that carbon and oxygen was produced in now long-dead stars, when they had finished fusing nearly all their hydrogen fuel into helium, and began fusing helium into heavier elements.
https://www.insidescience.org/news/more-finely-tuned-universe

J. Warner Wallace: FINE-TUNING OF THE FORCE STRENGTHS TO PERMIT LIFE AUGUST 3, 2014
Finely-Tuned Output of Stellar Radiation
Brandon Carter first discovered a remarkable relationship among the gravitational and electromagnetic coupling constants. If the 12th power of the electromagnetic strength were not proportional to the gravitational coupling constant then the photons produced by stars would not be of the right energy level to interact with chemistry and thus to support photosynthesis. Note how sensitive a proportion has to be when it involves the 12th power – a doubling of the electromagnetic force strength would have required an increase in the gravitational strength by a factor of 4096 in order to maintain the right proportion. Harnessing light energy through chemical means seems to be possible only in universes where this condition holds. If this is not strictly necessary for life, it might enter into the evidence against the multiverse in that it points to our universe being more finely-tuned than is strictly necessary.
https://crossexamined.org/fine-tuning-force-strengths-permit-life/

Kinga Nyíri Structural model of human dUTPase in complex with a novel proteinaceous inhibitor  12 March 2018
Fine-tuned regulation of nucleotide metabolism to ensure DNA replication with high fidelity is essential for proper development in all free-living organisms.
https://www.nature.com/articles/s41598-018-22145-8


1. Barrow, FITNESS OF THE COSMOS FOR LIFE,  Biochemistry and Fine-Tuning, page 352
2. Pavel Hobza: Structure, Energetics, and Dynamics of the Nucleic Acid Base Pairs: Nonempirical Ab Initio Calculations June 29, 1999 https://pubs.acs.org/doi/10.1021/cr9800255
3. https://assignmentpoint.com/tautomers/
4. Yitzhak Tor: On the Origin of the Canonical Nucleobases: An Assessment of Selection Pressures across Chemical and Early Biological Evolution 2013 Jun; 5. Libretext: DNA Structure
5. https://web.archive.org/web/20121130144326/http://creationsafaris.com/crev200411.htm

Further reading: 
The Proteasome hub: Fine-tuning of proteolytic machines according to cellular needs (ORGANIZED BY PROTEOSTASIS)
31 May, 2017
Several recent landmark findings show that an intricate regulation of proteasome function depends on cellular signals.
http://cost-proteostasis.eu/blog/event/the-proteasome-hub-fine-tuning-of-proteolytic-machines-according-to-cellular-needs-organized-by-proteostasis/

Fine Tuning Our Cellular Factories: Sirtuins in Mitochondrial Biology
8 June 2011
Sirtuins have emerged in recent years as critical regulators of metabolism, influencing numerous facets of energy and nutrient homeostasis.
http://www.cell.com/cell-metabolism/fulltext/S1550-4131(11)00184-7

Fine-Tuning of the Cellular Signaling Pathways by Intracellular GTP Levels
New York 2014
https://www.ncbi.nlm.nih.gov/pubmed/24643502

Fine-tuning of photosynthesis requires CURVATURE THYLAKOID 1-mediated thylakoid plasticity
January 26, 2018
http://sci-hub.ren/10.1104/pp.17.00863



Last edited by Otangelo on Tue 6 Jun 2023 - 15:22; edited 40 times in total

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Fine-tuning, which traditionally was an argument of design from cosmology, extends to biochemistry

https://reasonandscience.catsboard.com/t2591-biochemical-fine-tuning-essential-for-life#5623

Today, it is particularly striking to many scientists that cosmic constants, physical laws, biochemical pathways, and terrestrial conditions are just right for the emergence and flourishing of life. 1 It now seems that only a very restricted set of physical conditions operative at several major junctures of emergence could have opened the gateways to life.

Fine-tuning in biochemistry is represented by the strength of the chemical bonds that makes the universal genetic code possible. Neither transcription nor translation of the messages encoded in RNA and DNA would be possible if the strength of the bonds had different values. Hence, life, as we understand it today, would not have arisen. 2

Fine-tuning in biochemistry is represented in molecular biological terms by the strength of chemical bonds that make the universal genetic code possible. The messages coded in RNA and DNA would not be possible if the strengths of the bonds had different values. Hence, life, as we understand it today, would not have arisen.

As it happens, the average bond energy of a carbon–oxygen double bond is about 30 kcal per mol higher than that of a carbon–carbon or carbon–nitrogen double bond, a difference that reflects the fact that ketones normally exist as ketones and not as their enol-tautomers. If (in the sense of a “counterfactual variation”) the difference between the average bond energy of a carbon–oxygen double bond and that of a carbon–carbon and carbon–nitrogen double bond were smaller by a few kcal per mol, then the nucleobases guanine, cytosine, and thymine would exist as “enols” and not as “ketones,” and Watson–Crick base-pairing would not exist – nor would the kind of life we know.

It looks as though this is providing a glimpse of what might appear (to those inclined) as biochemical fine-tuning of life.

AmazingWatson–Crick base-pairing
The existence of Watson–Crick base-pairing in DNA and RNA is crucially dependent on the position of the chemical equilibria between tautomeric forms of the nucleobases.1 These equilibria in both purines and pyrimidines lie sharply on the side of amide- and imide-forms containing the (exocyclic) oxygen atoms in the form of carbonyl groups (C=O) and (exocyclic) nitrogen in the form of amino groups (NH2). The positions of these equilibria in a given environment are an intrinsic property of these molecules, determined by their physico-chemical parameters (and thus, ultimately, by the fundamental physical constants of this universe). The chemist masters the Herculean task of grasping and classifying the boundless diversity of the constitution of organic molecules by using the concept of the “chemical bond.” He pragmatically deals with the differences in the thermodynamic stability of molecules by using individual energy parameters, which he empirically assigns to the various types of bonds in such a way that he can simply add up the number and kind of bonds present in the chemical formula of a molecule and use their associated average bond energies to estimate the relative energy content of essentially any given organic molecule.

Now comes the striking interpretation of the Darwinism-inclined and indoctrinated mind :

Whatever biological phenomena appear fine-tuned can be interpreted in principle as the result of life having finetuned itself to the properties of matter through natural selection. Indeed, to interpret in this way what we observe in the living world is mainstream thinking within contemporary biology and biological chemistry.

Sometimes it strikes me how un-imaginative these folks are. They cannot imagine anything else beside NATURAL SELECTION. So the hero on the block strikes again. The multi-versatile mechanism propagated by Darwin explains and solves practically any issue and arising question of origins. Can't explain a phenomena in question ? NS did it.....  huh....

Conceive (through chemical reasoning) potentially natural alternatives to the structure of RNA; synthesize such alternatives by chemical methods; compare them with RNA with respect to those chemical properties that are fundamental to its biological function. Fortunately for this special case of the nucleic acids, it is not at all problematic to decide what the most important of these properties has to be: it must be the capability to undergo informational Watson–Crick base-pairing. The relevance of the perspective created in such a project will strongly depend on the specific choice of the alternatives’ chemical structures. The quest is to focus on systems deemed to
be potentially natural in the sense that they could have formed, according to chemical reasoning, by the very same type of chemistry that (under unknown circumstances) must have been operating on earth (or elsewhere) at the time when and at the place where the structure type of RNA was born. Candidates that lend themselves to this choice are oligonucleotide systems, the structures of which are derivable from (CH2O)n sugars (n = 4, 5, 6) by the type of chemistry that allows the structure of natural RNA to be derived from the C5-sugar ribose .

This approach is based on the supposition that RNA structure originated through a process that was combinatorial in nature with respect to the assembly and functional selection of an informational system within the domain of sugar-based oligonucleotides. In a way, the investigation is an attempt to mimic the selection filter of such a natural process by chemical means, irrespective of whether RNA first appeared in an abiotic or a biotic environment. In retrospect, the results of systematic experimental investigations carried out along these lines justify the effort

It is found that hexopyranosyl analogs of RNA (with backbones containing six carbons per sugar unit instead of five carbons and six-membered pyranose rings instead of five-membered furanose rings) do not possess the capability of efficient informational Watson–Crick base-pairing. Therefore, these systems could not have acted as functional competitors of RNA in nature’s the intelligent designers ( makes much more sense, doesnt't it ? Nature has no conscience nor mind to make choices ) choice of a genetic system, even though these sixcarbon alternatives of RNA should have had a comparable chance of being formed under the conditions that formed RNA. The reason for their failure revealed itself in chemical model studies: six-carbon-six-membered-ring sugars are found to be too bulky to adapt to the steric requirements of Watson–Crick base-pairing within oligonucleotide duplexes. In sharp contrast, an entire family of nucleic acid alternatives in which each member comprises repeating units of one of the four possible five-carbon sugars (ribose being one of them) turned out to be highly efficient informational base-pairing systems.

1. Barrow, FITNESS OF THE COSMOS FOR LIFE,  Biochemistry and Fine-Tuning, page 56
2. Barrow, FITNESS OF THE COSMOS FOR LIFE,  Biochemistry and Fine-Tuning, page 154

Biochemical fine-tuning - essential for life
https://reasonandscience.catsboard.com/t2591-biochemical-fine-tuning-essential-for-life#5623

Fine-tuning of the force of the hydrogen bonds that hold nucleotides together to form Watson-Crick base-pairing of DNA stands

https://reasonandscience.catsboard.com/t2591-biochemical-fine-tuning-essential-for-life#7845

Life uses just five nucleobases to make DNA and RNA. Two purines, and three pyrimidines. Purines use two rings with nine atoms, pyrimidines use just one ring with six atoms. Hydrogen bonding between purine and pyrimidine bases is fundamental to the biological functions of nucleic acids, as in the formation of the double-helix structure of DNA. This bonding depends on the selection of the right atoms in the ring structure. Pyrimidine rings consist of six atoms: 4 carbon atoms and 2 nitrogen atoms. Purines have nine atoms forming the ring: 5 carbon atoms and 4 nitrogen atoms.

Remarkably, it is the composition of these atoms that permit that the strength of the hydrogen bond that permits to join the two DNA strands and form Watson–Crick base-pairing, and well-known DNA ladder.  Neither transcription nor translation of the messages encoded in RNA and DNA would be possible if the strength of the bonds had different values. Hence, life, as we understand it today, would not have arisen.

Now, someone could say, that there could be no different composition, and physical constraints and necessity could eventually permit only this specific order and arrangement of the atoms. Now, in a recent science paper from 2019, Scientists explored how many different chemical arrangements of the atoms to make these nucleobases would be possible. Surprisingly, they found well over a million variants.   The remarkable thing is, among the incredible variety of organisms on Earth, these two molecules are essentially the only ones used in life. Why? Are these the only nucleotides that could perform the function of information storage? If not, are they perhaps the best? One might expect that molecules with smaller connected Carbon components should be easier for abiotic chemistry to explore.

According to their scientific analysis, the natural ribosides and deoxyribosides inhabit a fairly redundant ( in other words, superfluous, unnecessary, needless,  and nonminimal region of this space.  This is a remarkable find and implicitly leads to design. There would be no reason why random events would generate complex, rather than simple, and minimal carbon arrangements. Nor is there physical necessity that says that the composition should be so. This is evidence that a directing intelligent agency is the most plausible explanation. The chemistry space is far too vast to select by chance the right finely-tuned functional life-bearing arrangement.

In the mentioned paper, the investigators asked if other, perhaps equally good, or even better genetic systems would be possible.  Their chemical experimentations and studies concluded that the answer is no. Many nearly as good, some equally good, and a few stronger base-pairing analog systems are known. There is no reason why these structures could or would have emerged in this functional complex configuration by random trial and error. There is a complete lack of scientific-materialistic explanations despite decades of attempts to solve the riddle.

What we can see is, that direct intervention, a creative force, the activity of an intelligent agency, a powerful creator, is capable to have the intention and implement the right arrangement of every single atom into functional structures and molecules in a repetitive manner, in the case of DNA, at least 1,300,000  nucleotides to store the information to kick-start life, exclusively with four bases, to produce a storage device that uses a genetic code, to store functional, instructional, complex information, functional amino acids, and phospholipids to make membranes, and ultimately, life.  Lucky accidents, the spontaneous self-organization by unguided coincidental events, that drove atoms into self-organization in an orderly manner without external direction, chemical non-biological are incapable and unspecific to arrange atoms into the right order to produce the four classes of building blocks, used in all life forms.

Evidence shows that life depends on the right order and arrangement even of atoms !! 

Intelligent design advocates commonly point to the intrinsic order of molecules required to permit life the first go. Like the order of amino acids, arranged to permit polypeptides to fold into 3D arrangements that become functional.  But, in the following examples, I will demonstrate, that the precise order is required down even on a deeper level of the precise finely adjusted and tuned arrangement of atoms. 

According to an estimate made by engineers at Washington University, there are around 10^14 atoms in a typical human cell. Another way of looking at it is that this is 100,000,000,000,000 or 100 trillion atoms. . 1

A human cell hosts about 2 billion proteins. 2

Let's give a closer look at just one protein. Aspartate Carbamoyltransferase, one of the essential enzymes for the synthesis of DNA bases:

The active site 
of the enzyme is located where two individual catalytic subunits touch, so the position of the two subunits relative to one another is critical. Take just a moment to ponder the immensity of this enzyme. [/color]The entire complex is composed of over 40,000 atoms, each of which plays a vital role. The handful of atoms that actually perform the chemical reaction are the central players. But they are not the only important atoms within the enzyme--every atom plays a supporting pan. The atoms lining the surfaces between subunits are chosen to complement one another exactly, to orchestrate the shifting regulatory motions. The atoms covering the surface are carefully picked to interact optimally with water, ensuring that the enzyme doesn't form a pasty aggregate, but remains an individual, floating factory.

My comment: This is evidence, that the precise order to make life possible goes down to a prerequisite to arrange even atoms in the right order. The following will corroborate this even further !! 

Fine-tuning in biochemistry is represented by the strength of the chemical bonds that makes the universal genetic code possible. Neither transcription nor translation of the messages encoded in RNA and DNA would be possible if the strength of the bonds had different values. Hence, life, as we understand it today, would not have arisen. 3

As it happens, 
the average bond energy of a carbon-oxygen double bond is about 30 kcal per mol higher than that of a carbon-carbon or carbon-nitrogen double bond. If the difference between the average bond energy of a carbon-oxygen double bond and that of a carbon-carbon and carbon-nitrogen double bond were smaller by a few kcal per mol, then the nucleobases guanine, cytosine, and thymine would exist as “enols” and not as “ketones,” and Watson–Crick base-pairing would not exist – nor would the kind of life we know.

My comment: That means, the atom composition of the DNA nucleobases most be of the right atoms to guarantee the right hydrogen bond forces that permit Watson-Crick base-pairing.

Scientists recently explored the "chemical neighborhood" of nucleic acid analogs. Surprisingly, they found well over a million variants 1   Are DNA and RNA the only way to store this information? Or are they perhaps the best way? "There are two kinds of nucleic acids in biology ( RNA and DNA).  The remarkable thing is, among the incredible variety of organisms on Earth, these two molecules are essentially the only ones used in life. Why ? Are these the only molecules that could perform this function? If not, are they perhaps the best? Chemical space is, in principle, unlimited as at least one more atom can almost always be added to any given structure. 2    Any given structure space is limited by the input definitions, as well as by defined structural constraints.   One might expect that molecules with smaller connected Carbon components should be easier for abiotic chemistry to explore. According to scientific analysis, the natural ribosides and deoxyribosides inhabit a fairly redundant ( superfluous, unnecessary, needless) and nonminimal region of this space.

My comment: This is a remarkable find and implicitly leads to design. There would be no reason why stochastic events would generate complex, rather than simple, and minimal carbon arrangements. Nor is there physical necessity that says that the arrangement should be so. This is evidence that directing intelligent agency is the most plausible explanation. The chemistry space is far too vast to select by chance the right finely-tuned functional arrangement.

How can it be best explained, that life incorporates a solution to the need for information storage? A large number of possible motifs, both those which have thus-far been synthesized, which represent a minuscule fraction of the possible ones ,  argue that solutions in this chemical space are unlikely due to unguided stochastic natural events but rather the guiding hand of an intelligent designer.

From the standpoint of xeno and synthetic biology, could other, perhaps equally good, or even better genetic systems be devised? The answer to this question will require sophisticated and protracted chemical experimentation.Studies to date suggest that the answer could be no[/b]. Many nearly as good, some equally good, and a few stronger base-pairing analog systems are known.

My comment: Amazing!! RNA and DNA are probably an OPTIMALLY DESIGNED genetic system. This is clear evidence of design on an atomic level !! 
DNA molecules are asymmetrical, such property is essential in the processes of DNA replication and transcription. Bases need to be paired between pyrimidines and purines. In molecular biology, complementarity describes a relationship between two structures each following the lock-and-key principle.

Complementarity on an atomic level is the base principle of DNA replication and transcription as it is a property shared between two DNA or RNA sequences, such that when they are aligned antiparallel to each other, the nucleotide bases at each position in the sequences will be complementary, much like looking in the mirror and seeing the reverse of things. This complimentary base pairing is essential for cells to copy information from one generation to another. There is no reason why these structures could or would have emerged in this functional complex configuration by random trial and error processes. There is a complete lack of scientific-materialistic explanations despite decades of attempts to solve the riddle. 

Another interesting observation is that RNA and DNA use a five-membered ribose ring structure as a backbone element. It is found that six-membered ring with backbones containing six carbons per sugar unit instead of five carbons and six-membered pyranose rings instead of five-membered furanose rings do not possess the capability of efficient informational Watson–Crick base-pairing.

https://sci-hub.ren/https://pubs.acs.org/doi/10.1021/acs.jcim.9b00632



Last edited by Otangelo on Sun 27 Jun 2021 - 2:57; edited 5 times in total

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F.Rana Cell's design, page 119
Perfect Timing 
Exact fine-tuning is not limited to the structure of biomolecules. Sometimes the rate of biochemical processes is also meticulously refined. Recent studies indicate that the rate of messenger RNA and protein breakdown, two processes central to the cell's activity, are exquisitely regulated by the cell's machinery.

Shutting Down Production
Messenger RNA (mRNA) plays a central role in protein production. These molecules mediate the transfer of information from the nucleotide sequences of DNA to the amino acid sequences of proteins. The cell's machinery copies mRNA from DNA only when the cell needs the protein encoded by a particular gene housed in the DNA. When that protein is not needed, the cell shuts down production. This practice is a matter of efficiency. In this way, the cell makes only the mRNAs and consequently the proteins it needs.  Once produced, mRNAs continue to direct the production of proteins at the ribosome. Fortunately, mRNA molecules have limited stability and only exist intact for a brief period of time before they break down. This short lifetime benefits the cell. If mRNA molecules unduly persisted, then they would direct the production of proteins at the ribosome beyond the point the cell needs. Overproduction would not only be wasteful, but it would also lead to the coexistence of proteins that carry out opposed functions within the cell. The careful control of mRNA levels is necessary for the cell to have the right amounts of proteins at the right time. Unregulated protein levels would compromise life.  Until recently, biochemists thought regulation of mRNA levels (and hence protein levels) occurred when the cell's transcriptional machinery carefully controlled mRNA production. New research, however, indicates that mRNA breakdown also helps regulate its level.  Prior to this work, biochemists thought that the degradation of mRNA was influenced only by abundance, size, nucleotide sequence, and so forth. However, this perspective was incorrect. The breakdown of mRNA molecules is not random but precisely orchestrated. Remarkably, messenger RNA molecules, which correspond to proteins that  are part of the same metabolic pathways, have virtually identical decay rates. The researchers also found that mRNA molecules, which specify proteins involved in the cell's central activities, have relatively slow breakdown rates. Proteins only needed for transient cell processes are encoded by mRNAs with rapid rates of degradation. The decay of mRNA molecules is not only fine-tuned but also displays an elegant biochemical logic that bespeaks of intelligence.

Tagged for Destruction
Proteins, which play a role in virtually every cell structure and activity, are constantly made—and destroyed—by the cell. Those that take part in highly specialized activities within the cell are manufactured only when needed. Once these proteins have outlived their usefulness, the cell breaks them down into their constitutive amino acids. The removal of unnecessary proteins helps keep the cell's interior free of clutter.  On the other hand, proteins that play a central role in the cell's operation are produced on a continual basis. After a period of time, however, these proteins inevitably suffer damage from wear and tear and must be destroyed and replaced with newly made proteins. It's dangerous for the cell to let damaged proteins linger.  Once a protein is damaged, it's prone to aggregate with other proteins. These aggregates disrupt cellular activities. Protein degradation and turnover, in many respects, are just as vital to the cell's operation as protein production. And, as is the case for mRNAs, protein degradation is an exacting, delicately balanced process.  This complex undertaking begins with ubiquitination. When damaged, proteins misfold, adopting an unnatural three-dimensional shape. Misfolding exposes amino acids in the damaged protein's interior. These exposed amino acids are recognized by E3 ubiquitin ligase, an enzyme that attaches a small protein molecule (ubiquitin) to the damaged protein. Ubiquitin functions as a molecular tag, informing the cell's machinery that the damaged protein is to be destroyed. Severely damaged proteins receive multiple tags.

To the Rescue
Ubiquitination is a reversible process with de-ubiquitinating enzymes removing inappropriate ubiquitin labels. This activity prevents the cell's machinery from breaking down fully functional proteins that may have been accidentally tagged for destruction because E3 ubiquitin ligase occasionally makes mistakes.  A massive protein complex, a proteasome, destroys damaged ubiquitinated proteins, functioning like the cell's garbage can. The overall molecular architecture of the proteasome consists of a hollow cylinder topped with a lid that can exist in either an opened or closed conformation. Protein breakdown takes place within the cylinder's interior. The lid portion of the proteasome controls the entry of ubiquitinated proteins into the cylinder.  The proteasome lid contains de-ubiquitinating activity. If a protein has only one or two ubiquitin tags, it's likely not damaged and the lid will remove the tags rescuing the protein from destruction. The cell's machinery then recycles the rescued protein. If, on the other hand, the protein has several ubiquitin tags, the lid cannot remove them all and shuttles the damaged protein entry into the proteasome cylinder.  The proteasome lid regulates a delicate balance between destruction and rescue, ensuring that truly damaged proteins are destroyed and proteins that can be salvaged escape unnecessary degradation. The cell's protein degradation system, like messenger RNA breakdown, displays fine-tuning and elegant biochemical logic that points to a Creator's handiwork.
https://3lib.net/book/1084198/d6299b

My comment: Must regulation, delicate balance and fine-tuning when a protein needs to be expressed, and when degraded, not be preprogrammed, and is it not a mechanism life-essential, and required to be fully functional right from the start when life began? The paradigm of Darwinism leads to the conclusion and belief that gradual, stepwise evolutionary change can give rise to all molecular functions, but evidence shows that life in ALL its forms is interdependent, functions depend on the "joint-venture" of various different cell types, or organs, and had to emerge together, as a whole, not individually.  The regulation of protein expression had to emerge together with the capacity of protein degradation when required, and the recognition and regulation mechanism of both functions.  This is strong evidence of intelligent design.

Ola Hössjer  Using statistical methods to model the fine-tuning of molecular machines and systems 2020-06-22
Biological systems present fine-tuning at different levels, e.g. functional proteins, complex biochemical machines in living cells, and cellular networks. This paper describes molecular fine-tuning, how it can be used in biology, and how it challenges conventional Darwinian thinking. We also discuss the statistical methods underpinning finetuning and present a framework for such analysis.

Fine-tuning has obtained much attention in physics, and many studies have been accomplished since Brandon Carter presented his first results at the conference honoring Copernicus’s 500th birthday (Carter, 1974). Luke Barnes has published a good review paper on the fine-tuning of the universe (Barnes, 2012), and Lewis and Barnes wrote an up to date book (2016). This naturally raises the question whether it is appropriate to introduce and address fine-tuning in biology as well. The term fine-tuning is used to characterize sensitive dependencies of functions or properties on the values of certain parameters (cf. Friederich, 2018). While technological devices are
fine-tuned products of actual engineers and manufacturers who designed and built them, only sensitivity with respect to the values of certain parameters or initial conditions are considered sufficient in the present paper. We define fine-tuning as an object with two properties: it must 

a) be unlikely to have occurred by chance, under the relevant probability distribution (i.e. complex), and 
b) conform to an independent or detached specification (i.e. specific). 

The notion of design is also widely used within both historic and contemporary science (Thorvaldsen and Øhrstrøm, 2013). The concept will need a description for its use in our setting. A design is a specification or plan for the construction of an object or system, or the result of that specification or plan in the form of a product. The very term design is from the Medieval Latin word ‘‘designare” (denoting ‘‘mark out, point out, choose”); from ‘‘de” (out) and ‘‘signum” (identifying mark, sign). Hence, a public notice that advertises something or gives information. The design usually has to satisfy certain goals and constraints. It is also expected to interact with a certain environment, and thus be realized in the physical world. Humans have a powerful intuitive understanding of design that precedes modern science. Our common intuitions invariably begin with recognizing a pattern as a mark of design. The problem has been that our intuitions about design have been unrefined and pre-theoretical. For this reason, it is relevant to ask ourselves whether it is possible to turn the tables on this disparity and place those rough and pre-theoretical intuitions on a firm scientific foundation. Fine-tuning and design are related entities. Fine-tuning is a bottom-up method, while design is more like a top-down approach. Hence, we focus on the topic of fine-tuning in the present paper and address the following questions: Is it possible to recognize fine-tuning in biological systems at the levels of functional proteins, protein groups and cellular networks? Can fine-tuning in molecular biology be formulated using state of the art statistical methods, or are the arguments just ‘‘in the eyes of the beholder”?

Main results and discussion
In this section, we will present and discuss some relevant observations from experimental biology. This will be done in the light of the theory of stochastic models, outlined in Section 2. More specifically, we will identify events A whose probability is very low under naturalistic stochastic models, and argue that these represent extreme examples of fine-tuning.

4.1. Functional proteins
Natural proteins are known to fold only to a limited number of folds. The designability of a structure is defined as the number of sequences folding to the structure (Zhang et al., 2014). Some of these folds are frequently occurring and often referred to as highly designable, whereas some others are rarely observed and are less designable. Li et al. (1996) first introduced this concept of protein designability. One interesting aspect of their study was that the structures differed strongly in designability, and highly designable structures were only a small fraction of all structures. An important goal is to obtain an estimate of the overall prevalence of sequences adopting functional protein folds, i.e. the right folded structure, with the correct dynamics and a precise active site for its specific function. Douglas Axe worked on this question at the Medical Research Council Centre in Cambridge. The experiments he performed showed a prevalence between 1 in 10^50 to 1 in 10^74 of protein sequences forming a working domain-sized fold of 150 amino acids (Axe, 2004). Hence, functional proteins require highly organised sequences. Though proteins tolerate a range of possible amino acids at some positions in the sequence, a random process producing amino-acid chains of this length would stumble onto a functional protein only about one in every 10^50 to 10^74 attempts due to genetic variation. This empirical result is quite analog to the inference from fine-tuned physics. That is, we may regard the space X of all possible proteins as the outcomes of a stochastic model, where each outcome is a string of letters (amino acids). The prevalence is the probability of the event Ap that a randomly chosen amino acid sequence leads to a functional protein (or more generally a protein with some characteristic patterns), whereas hp involves all biochemical constants of relevance for protein formation. 

Protein complexes
Proteins rarely work alone. They can interact with a variety of different molecules, but it is their simultaneous interactions with one another at the same location that account for many of the functions of the cell (Jones and Thornton, 1996). Proteins in a protein complex are linked by non-covalent protein–protein interactions. Protein complexes are a form of quaternary structure. These complexes are fundamental in many biological processes
and together they form various types of molecular machinery that perform a vast array of biological functions. Protein assemblies are at the basis of numerous biological machines by performing actions that none of the individual proteins would be able to do. There are thousands, perhaps millions of different types and states of proteins in a living organism, and the number of possible interactions between them is enormous. Proper assembly of multiprotein complexes is important, and change from an ordered to a disordered state leads to a transition from function to dysfunction of the complex. Some protein complexes can be quite constant and exist for the lifetime of the cell while others can be transient, accumulated for some purpose and broken down when no longer needed. A Behe-system of irreducible complexity was mentioned in Section 3. It is composed of several well-matched, interacting modules that contribute to the basic function, wherein the removal of any one of the modules causes the system to effectively cease functioning. Behe does not ignore the role of the laws of nature. Biology allows for changes and evolutionary modifications. Evolution is there, irreducible design is there, and they are both observed. The laws of nature can organize matter and force it to change. Behe’s point is that there are some irreducibly complex systems that cannot be produced by the laws of nature: ‘If a biological structure can be explained in terms of those natural laws [reproduction, mutation and natural selection] then we cannot conclude that it was designed. . . however, I have shown why many biochemical systems cannot be built up by natural selection working on mutations: no direct, gradual route exist to these irreducible complex systems, and the laws of chemistry work strongly against the undirected development of the biochemical systems that make molecules such as AMP1” (Behe, 1996, p. 203).

Then, even if the natural laws work against the development of these ‘‘irreducible complexities”, they still exist. The strong synergy within the protein complex makes it irreducible to an incremental process. They are rather to be acknowledged as fine-tuned initial conditions of the constituting protein sequences. These structures are biological examples of nano-engineering that surpass anything human engineers have created. Such systems
pose a serious challenge to a Darwinian account of evolution, since irreducibly complex systems have no direct series of selectable intermediates

Cellular networks
As Denis Noble states, biological systems function as a full orchestra with its different elements playing ensemble the score of life (Noble, 2006). Protein complexes perform their biological functions in a cooperative manner through their participation in many biological processes and networks, from the nucleus to the cell membrane. Cellular networks are also known to contain feedback loops and cycles. A stochastic model with cellular networks as outcomes is exceedingly complex. However, Bayesian models provide one of the most flexible frameworks for modeling such networks in terms of Dynamic Bayesian networks. In order to describe these structures, modern textbooks often utilize the pedagogical similarities between the cell’s network and a modern city, or ‘‘smart city” (Daempfle, 2016). Studying protein interaction networks of all proteins in an organism (the ‘‘interactomes”) remains one of the major challenges in modern biology, and constitutes the objective of systems biology. Statistical methods to reconstruct cellular networks is a vast and fast developing area of research, including Bayesian networks, Gaussian graphical models and graph-based methods for data from experimental interventions and perturbations (Markowetz and Spang, 2007). Random graphs may also be used for modeling cellular networks.These resulting graphs should capture the fact that genes and gene products are connected in highly organized networks of information flow through the cell, which themselves do not work in isolation. We observe correlations between genes by the presence of other genes. 

https://sci-hub.st/https://www.sciencedirect.com/science/article/pii/S0022519320302071

P. Kurian How quantum entanglement in DNA synchronizes double-strand breakage by type II restriction endonucleases 2017 Feb 21
The genomes of all cellular lifeforms and several large DNA viruses encode multiple proteins whose function is to repair the damaged DNA

DNA repair is essential for any organism, and for cellular function. Maintaining the genetic stability that an organism needs for its survival requires not only an extremely accurate mechanism for replicating DNA, but also mechanisms for repairing the many accidental lesions that occur continually in DNA.

DNA repair as a whole is a highly complex phenomenon. The repair mechanisms can be classified into several distinct, if not completely independent, major pathways that differ with regard to the level at which the lesions in damaged DNA are reversed or removed by the repair machinery

Endonucleases are a type of enzyme that cuts the phosphor-diester bond—the backbone of DNA—in a strand of DNA or RNA. Type I cuts the DNA bond randomly. There are many other specific versions called “restriction enzymes” that cut only at very specific sequences. Type III has been studied the most for its relation to electric DNA and cuts very specifically.

When connected to DNA, Endonuclease III changes its shape allowing the iron and sulfur atoms to give up electrons increasing its charge. This shape alteration makes the enzyme increase its hold on the DNA. The released electron travels along the DNA wire until it meets another Endonuclease III molecule attached to the DNA. The secondEndonuclease III molecule takes up the electron from the DNA. Taking up this electron, the second enzyme loosens its grip on the DNA.

As the electron travels along the DNA wire, it is stopped if there is a damaged spot, thus identifying a problem. When the error is identified, both of the repair molecules stay attached to the DNA wire on either side of the error, identifying a trouble spot. In fact, Endonuclease III does more. It helps communicate with other proteins, such as MutY, that come and fix the mutation.

This mechanism of exchanging electrons has now been shown to be extremely important in many techniques for repairing DNA. It, also, occurs occurs with many other repair proteins.

Now this is truly amazing:

How quantum entanglement in DNA synchronizes double-strand breakage by type II restriction endonucleases

Type II endonucleases, the largest class of restriction enzymes, induce DNA double-strand breaks by attacking phosphodiester bonds, the mechanism by which simultaneous cutting is coordinated between the catalytic centers.

The purpose of the orthodox class of these enzymes is to catalyze a double-strand break without the use of an external chemical energy source like ATP. Our hypothesis has been that these enzymes recruit this energy from coherent oscillations in the DNA substrate. In the absence of direct experimental confirmation, the computational data presented here provide tentative support that the coherent oscillations in six- and eight-base-pair DNA target sequences may be finely tuned for the energy sequestration that is required to initiate synchronized double-strand breakage.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4746125/

My comment: Another amazing example of fine-tuning and the use of quantum mechanics in biochemistry !!  Its origin, by unguided natural events, or intelligent design ?

Biochemical fine-tuning - essential for life Nihms-10



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The four ATGC nucleobases have perfect fits and sizes to have life-essential Watson-Crick base-pairing, finely tuned to do their job. How comes? 

https://reasonandscience.catsboard.com/t2591-biochemical-fine-tuning-essential-for-life#9172

Biochemical fine-tuning - essential for life
https://reasonandscience.catsboard.com/t2591-biochemical-fine-tuning-essential-for-life

John BarrowFITNESS OF THE COSMOS FOR LIFE,  Biochemistry and Fine-Tuning, page 56
Amazing Watson–Crick base-pairing
The existence of Watson–Crick base-pairing in DNA and RNA is crucially dependent on the position of the chemical equilibria between tautomeric forms of the nucleobases. These equilibria in both purines and pyrimidines lie sharply on the side of amide- and imide-forms containing the (exocyclic) oxygen atoms in the form of carbonyl groups (C=O) and (exocyclic) nitrogen in the form of amino groups (NH2). The positions of these equilibria in a given environment are an intrinsic property of these molecules, determined by their Physico-chemical parameters (and thus, ultimately, by the fundamental physical constants of this universe).  Whatever biological phenomena appear fine-tuned can be interpreted in principle as the result of life having finetuned itself to the properties of matter through natural selection. Indeed, to interpret in this way what we observe in the living world is mainstream thinking within contemporary biology and biological chemistry.

My comment: It strikes me how un-imaginative these folks are. They cannot imagine anything else besides NATURAL SELECTION. So the hero on the block strikes again. The multi-versatile mechanism propagated by Darwin explains and solves practically any issue and arising question of origins. Can't explain a phenomenon in question? natural selection must be the hero on the block. It did it.....  huh...

Conceive (through chemical reasoning) potentially natural alternatives to the structure of RNA; synthesize such alternatives by chemical methods; compare them with RNA with respect to those chemical properties that are fundamental to its biological function. Fortunately for this special case of the nucleic acids, it is not at all problematic to decide what the most important of these properties has to be: it must be the capability to undergo informational Watson–Crick base-pairing.  It is found that hexopyranosyl analogs of RNA (with backbones containing six carbons per sugar unit instead of five carbons and six-membered pyranose rings instead of five-membered furanose rings) do not possess the capability of efficient informational Watson–Crick base-pairing. Therefore, these systems could not have acted as functional competitors of RNA in nature’s choice of a genetic system, even though these six-carbon alternatives of RNA should have had a comparable chance of being formed under the conditions that formed RNA. 

My comment:  Nature does not make choices. Only intelligent agents with intent, will, and foresight do. The authors cannot resort to natural selection either, since at this stage, in the history of life, there was nothing to be selected.

The reason for their failure revealed itself in chemical model studies: six-carbon-six-membered-ring sugars are found to be too bulky to adapt to the steric requirements of Watson–Crick base-pairing within oligonucleotide duplexes. In sharp contrast, an entire family of nucleic acid alternatives in which each member comprises repeating units of one of the four possible five-carbon sugars (ribose being one of them) turned out to be highly efficient informational base-pairing systems. 
https://3lib.net/book/449297/8913bb

Remarkably, it is the composition of these atoms that permit the strength of the hydrogen bond that permits to join the two DNA strands and form Watson–Crick base-pairing, and well-known DNA ladder.  Neither transcription nor translation of the messages encoded in RNA and DNA would be possible if the strength of the bonds had different values. Hence, life, as we understand it today, would not have arisen. As it happens, the average bond energy of a carbon-oxygen double bond is about 30 kcal per mol higher than that of a carbon-carbon or carbon-nitrogen double bond, a difference that reflects the fact that ketones normally exist as ketones and not as their enol-tautomers. If (in the sense of a “counterfactual variation”) the difference between the average bond energy of a carbon-oxygen double bond and that of a carbon-carbon and carbon-nitrogen double bond were smaller by a few kcal per mol, then the nucleobases guanine, cytosine, and thymine would exist as “enols” and not as “ketones,” and Watson–Crick base-pairing would not exist – nor would the kind of life we know.

It looks as though this is providing a glimpse of what might appear (to those inclined) as biochemical fine-tuning of life.

Henderson James Cleaves One Among Millions: The Chemical Space of Nucleic Acid-like Molecules  September 13, 2019 1

Biology encodes hereditary information in DNA and RNA, which are finely tuned to their biological function and modes of biological production. Indeed, other nucleic acid-like polymers can play similar roles to natural nucleic acids both in vivo and in vitro, yet despite remarkable advances over the last few decades, much remains unknown regarding which structures are compatible with molecular information storage. Chemical space describes the structures and properties of molecules that could exist within a given molecular formula or another classification system. 

Could other, perhaps equally good, or even better genetic systems be devised? The answer to this question will require sophisticated and protracted chemical experimentation. Studies to date suggest that the answer could be no. Many nearly as good, some equally good, and a few stronger base-pairing analogue systems are known.

1. https://sci-hub.yncjkj.com/10.1021/acs.jcim.9b00632

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Sequence elements and modifications of the initiator tRNA distinguish it from the elongator methionyl tRNA and help it to perform its varied tasks. These identity elements appear to finely tune the structure of the initiator tRNA, and growing evidence suggests that the body of the tRNA is involved in transmitting the signal that the start codon has been found to the rest of the pre-initiation complex.
https://www.sciencedirect.com/science/article/pii/S0014579309009600

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Intelligent Design predicts that more and more instructional complex genetic and epigenetic information will be discovered and unraveled, that directs the making and operation of interdependent, irreducibly complex molecular machines, assembly lines, and biological integrated systems, that are finely tuned and adjusted to perform specific functions and tasks, that might be essential for the higher operation of biological, self-replicating cells, and multicellular organisms. Fine-tuning has indeed extended to biochemistry. Nucleobases are fine-tuned to permit Watson-Crick hydrogen bonding, which is essential to have the DNA ladder. Genes are the information-bearing molecules used in life. Fine-tuning now extends as well to Cell-membranes, Cell signaling, and the structure of ATP synthase energy turbines.  

Futerman A.H.:  The fine-tuning of cell membrane lipid bilayers accentuates their compositional complexity  18 February 2021
Cell membranes are now emerging as finely tuned molecular systems. The structural, compositional, and functional complexity of lipid bilayers often catches cell and molecular biologists by surprise. We propose that describing lipid bilayers as “finely-tuned molecular assemblies” best portrays their complexity and function. Fine-tuning in cosmology and physics is the idea that certain parameters of the universe must occur within very stringent limits in order to support life. These parameters include the sensitive dependencies of the values of certain physical parameters, conditions in the early universe, and the physical laws, all of which are fine-tuned to a remarkable degree. The term “finetuning” is used much less frequently in biology than in cosmology and physics, and even when it is used, the sense is that fine-tuning is used to describe “precisely or tightly regulated mechanisms,” or to define the number of constraints that can be applied before a deleterious effect is observed on the system under study In the current essay, we propose that the time is ripe for a shift in the conceptual landscape concerning lipid bilayers in cell membranes. We will suggest that current models of lipid bilayer structure and function all fall far short inasmuch as they do not take into account the unexpected compositional complexity of the lipid (and protein) constituents of membranes. Lipid bilayers can best be described as “finely-tuned molecular assemblies.” To support this suggestion, we will consider three properties of lipid bilayers that appear to fulfill the criteria of fine-tuning, namely their composition, the distribution of lipids within and across bilayers, and the specific interactions of membrane lipids with membrane proteins. 

The composition of membrane lipids is much more complex than once thought. Lipidomics (herein described as “systems-level identification and quantitation of thousands of pathways and networks of cellular lipids, molecular species and their interactions with other lipids, proteins and other moieties in vivo”) has revealed an enormous combinatorial complexity of lipid species: the LIPID MAPS Structure Database suggests that >1,100,000 potential lipid structures may exist in nature. Clearly, not all of these lipids are found in lipid bilayers, although 8,000 lipid species have been identified, for instance, in whole human platelets, and up to 400 in isolated plasma membranes (PMs). 

MEMBRANE LIPID BILAYER COMPOSITION, AND INTERACTIONS BETWEEN MEMBRANE PROTEINS AND LIPIDS ARE FINELY TUNED 
Membranes of course also contain many proteins with recent estimates suggesting that about 25% (∼5000 proteins) of the human genome encodes membrane proteins. The transmembrane domains (TMDs) of these proteins perfectly match, in terms of hydrophobic length and helical surface area, the asymmetric distribution of lipids on each side of the bilayer.  Lipid–protein interactions are now known to be highly specific, highly regulated, and strongly influenced by lipid composition and distribution. Three properties of lipid bilayers' composition, the distribution of lipids within and across bilayers, and the specific interactions of membrane lipids with membrane components are entirely consistent with our suggestion that cell membrane lipid bilayers can be described as “finely-tuned molecular assemblies.” “Fine-tuning” refers to the low level of tolerance towards change for many of these properties, and “molecular assembly” refers to the unanticipated complexity of membrane bilayers and the multitude of specific interactions between members of the assembly. This description prompts testable hypotheses related to explicit aspects of bilayer composition and function. For instance, this concept suggests that lipid composition, even of low-abundance lipids, is of functional relevance for membrane function, and therefore changing composition, even by a small amount, should affect bilayer properties. Likewise, the relationship between membrane proteins and the lipids that bind to them could be experimentally examined by changing the lipid environment or altering the lipid-binding motif in the protein. Finally, altering lipid composition of each half of the bilayer is likely to affect biophysical properties, either in one half only or in both halves, if acyl chain interdigitation occurs (which in turn depends on lipid composition, namely the acyl chain length). While such experimental approaches could have been proposed based on earlier models of lipid bilayers, our fine-tuning model implies that considerably smaller changes than would have previously been anticipated are likely to have major effects on lipid bilayer properties and function. Recently, a somewhat similar concept about the structure of membrane lipid bilayers was put forward with the suggestion that membrane lipids and proteins are part of a “molecular machine.” We fully encompass this idea but additionally highlight the sublime nature of cell membrane lipid bilayers (á la Newton who stated that “the universe is sublime”) and join Aristotle who proclaimed over two millennia ago that “in all things of nature there is something of the marvelous”; might we be so bold as to suggest that “in all aspects of lipid bilayers, there is something of the marvelous”?

Koichi Furukawa: Fine-tuning of cell signals by glycosylation 22 May 2012
Carbohydrates on the glycoproteins and glycosphingolipids expressed on the cell surface membrane play crucial roles in the determination of cell fates by being involved in the fine tuning of cell signalling as reaction molecules in the front line to various extrinsic stimulants. Glycosylation’ plays as a fine-tuner of cell signaling. Membrane proteins accumulate in lipid rafts and efficiently transduce cell signals during the signal introduction, and glycosphingolipids modulate these processes. 2

ATP synthase
Subtle, sub-Ångström conformational changes in the α subunit that control the position of an arginine residue (R373) in the catalytic site in the beta subunit play a crucial role in stabilizing the transition state; sub-Ångström changes in the side-chain result in loss of three orders of magnitude of catalytic activity. 1 This sensitivity is critical to the role of this arginine residue in controlling the rate of ATP hydrolysis, as confirmed experimentally and by hybrid quantum mechanics/molecular mechanics calculations. The use of quantifiable values such as “sub-Ångström” reinforces the notion of tolerance in biological systems, that is, the range of variation permitted to maintain a specific property. 

https://www.youtube.com/watch?v=ddkP-QRZTl8


1. Yukawa, A., Iino, R., Watanabe, R., Hayashi, S., & Noji, H. (2015). Key chemical factors of arginine finger catalysis of F1-ATPase clarified by an unnatural amino acid mutation. Biochemistry, 54, 472–480
2. Koichi Furukawa: Fine tuning of cell signals by glycosylation 22 May 2012
3. Futerman A.H.:  The fine-tuning of cell membrane lipid bilayers accentuates their compositional complexity  18 February 2021

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C S Downes: Fine tuning of DNA repair in transcribed genes: mechanisms, prevalence and consequences  1993 Mar;15
Cells fine-tune their DNA repair, selecting some regions of the genome in preference to others. In the paradigm case, excision of UV-induced pyrimidine dimers in mammalian cells, repair is concentrated in transcribed genes, especially in the transcribed strand. This is due both to chromatin structure being looser in transcribing domains, allowing more rapid repair, and to repair enzymes being coupled to RNA polymerases stalled at damage sites; possibly other factors are also involved. Some repair-defective diseases may involve repair-transcription coupling: three candidate genes have been suggested. However, preferential excision of pyrimidine dimers is not uniformly linked to transcription. In mammals it varies with species, and with cell differentiation. In Drosophila embryo cells it is absent, and in yeast, the determining factor is nucleosome stability rather than transcription. Repair of other damage departs further from the paradigm, even in some UV-mimetic lesions. No selectivity is known for repair of the very frequent minor forms of base damage. And the most interesting consequence of selective repair, selective mutagenesis, normally occurs for UV-induced, but not for spontaneous mutations. The temptation to extrapolate from mammalian UV repair should be resisted.
https://pubmed.ncbi.nlm.nih.gov/8489527/

Kino Kusama: Dot6/Tod6 degradation fine-tunes the repression of ribosome biogenesis under nutrient-limited conditions 18 March 2022
Ribosome biogenesis (Ribi) is a complex and energy-consuming process, and should therefore be repressed under nutrient-limited conditions to minimize unnecessary cellular energy consumption. In yeast, the transcriptional repressors Dot6 and Tod6 are phosphorylated and inactivated by the TORC1 pathway under nutrient-rich conditions, but are activated and repress ∼200 Ribi genes under nutrient-limited conditions. However, we show that in the presence of rapamycin or under nitrogen starvation conditions, Dot6 and Tod6 were readily degraded by the proteasome in a SCFGrr1 and Tom1 ubiquitin ligase-dependent manner, respectively. Moreover, promiscuous accumulation of Dot6 and Tod6 excessively repressed Ribi gene expression as well as translation activity and caused a growth defect in the presence of rapamycin. Thus, we propose that degradation of Dot6 and Tod6 is a novel mechanism to ensure an appropriate level of Ribi gene expression and thereby fine-tune the repression of Ribi and translation activity for cell survival under nutrient-limited conditions.
https://www.sciencedirect.com/science/article/pii/S2589004222002565

Stephin J. Vervoort: The PP2A-Integrator-CDK9 axis fine-tunes transcription and can be targeted therapeutically in cancer May 17, 2021
Int-PP2A opposes CDK9 at the phosphorylation level to fine-tune transcription. We reveal how RNAPII-driven transcription is fine-tuned through the PP2A-Integrator-CDK9 axis. PP2A recruitment via INTS6 regulates steady-state transcription and is required to fine-tune acute transcriptional responses to pro-inflammatory and mitogenic stimuli.
https://www.cell.com/cell/fulltext/S0092-8674(21)00502-X?_returnURL=https%3A%2F%2Flinkinghub.elsevier.com%2Fretrieve%2Fpii%2FS009286742100502X%3Fshowall%3Dtrue

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Marco V. José: On the Importance of Asymmetry in the Phenotypic Expression of the Genetic Code upon the Molecular Evolution of Proteins 11 June 2020
Aminoacyl-tRNA synthetases (aaRSs) are responsible for implementing the standard genetic code (SGC) by specifically amino-acylating only its cognate transfer RNA (tRNA), thereby linking an amino acid with its corresponding anticodon triplets. tRNAs molecules bind each codon with its anticodon. To understand the meaning of symmetrical/asymmetrical properties of the SGC, we designed synthetic genetic codes with known symmetries and with the same degeneracy of the SGC. We determined their impact on the substitution rates for each amino acid under a neutral model of protein evolution. We prove that the phenotypic graphs of the SGC for codons and anticodons for all the possible arrangements of nucleotides are asymmetric and the amino acids do not form orbits. In the symmetrical synthetic codes, the amino acids are grouped according to their codonicity, this is the number of triplets encoding a given amino acid. Both the SGC and symmetrical synthetic codes exhibit a probability of occurrence of the amino acids proportional to their degeneracy. Unlike the SGC, the synthetic codes display a constant probability of occurrence of the amino acid according to their codonicity. The asymmetry of the phenotypic graphs of codons and anticodons of the SGC, has important implications on the evolutionary processes of proteins.

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Odds to select the first interactome of the first progenitor cell of all life

In order to have a functional interactome in a first hypothesized minimal cell, able to free living and self-replicating, many hurdles would have to be overcome, and many choices made. First, amongst an infinitude of molecules floating on the early earth, only a restricted and specified set of molecules are employed as building blocks to make up living cells. They have to be chosen. In order to have a minimal protein set, that would be synthesized by the first progenitor, the right nucleotides, amino acid set, and genetic code would have to be selected. Below, I expose what that entails. 

H. James Cleaves 2nd (2015): ‘‘Structure space’’ represents the number of molecular structures that could exist given specific defining parameters. For example, the total organic structure space, the druglike structure space, the amino acid structure space, and so on. Many of these chemical spaces are very large. 

Selecting the right nucleotides:
W. Patrick Walters (1998): There are perhaps millions of chemical ‘libraries’ that a trained chemist could reasonably hope to synthesize. Each library can, in principle, contain a huge number of compounds – easily billions.  A ‘virtual chemistry space’ exists that contains perhaps 10^100 possible molecules 

Andro C. Rios (2014): The native bases of RNA and DNA are prominent examples of the narrow selection of organic molecules upon which life is based. How did nature “decide” upon these specific heterocycles? Evidence suggests that many types of heterocycles could have been present on the early Earth. The prebiotic formation of polymeric nucleic acids employing the native bases remains a challenging problem. The structural space, restricted to the molecular formula of the core RNA riboside includes a large number of possible isomers. In the formula range from BC3H7O2 to BC5H9O4 (RNA’s)  each of the isomers could yield many stereo- and macromolecular linkage isomers, leading ultimately to perhaps billions of nucleic acid polymer types potentially capable of supporting base-pairing. Only a subset of these structural and stereoisomers would lead to stable base-pairing systems.

Selecting the first genome
In vast "sequence space" (amongst trillions of possible sequences, rare are the ones that provide function) The simplest free-living bacteria is P.Ubique.  These organisms get by with about 1,300 genes and 1,308,759 base pairs and code for 1,354 proteins. If a chain could link up, what is the probability that the code letters might by chance be in some order which would be a usable gene, usable somewhere—anywhere—in some potentially living thing? If we take a model size of 1,200,000 base pairs, the chance to get the sequence randomly would be 4^1.200,000 or 10^722,000

Selecting the genetic code
S. J. Freeland  (1998): Statistical and biochemical studies of the genetic code have found evidence of nonrandom patterns in the distribution of codon assignments. It has, for example, been shown that the code minimizes the effects of point mutation or mistranslation: erroneous codons are either synonymous or code for an amino acid with chemical properties very similar to those of the one that would have been present had the error not occurred. If we employ weightings to allow for biases in translation, then only 1 in every million random alternative codes generated is more efficient than the natural code. We thus conclude not only that the natural genetic code is extremely efficient at minimizing the effects of errors, but also that its structure reflects biases in these errors. 

Selecting the 20 proteinogenic amino acids
Science is clueless about how and why specifically 20 amino acids are incorporated into the genetic code to make proteins. Why 20, and not more or less? ( in some rare cases, 22) considering that many different ones could have been chosen? Stanley Miller (1981): There are only twenty amino acids that are coded for in protein synthesis, along with about 120 that occur by post-translational modifications. Yet there are over 300 naturally-occurring amino acids known, and thousands of amino acids are possible. The question then is - why were these particular 20 amino acids selected during the process that led to the origin of the most primitive organism?. Why Are beta, gamma and theta Amino Acids absent? The selection of a-amino acids for protein synthesis and the exclusion of the beta, gamma, and theta amino acids raises two questions. First, why does protein synthesis use only one type of amino acid and not a mixture of various α, β, γ, δ… acids? Second, why were the a-amino acids selected? The present ribosomal peptidyl transferase has specificity for only a-amino acids. Compounds with a more remote amino group reportedly do not function in the peptidyl transferase reaction. The ribosomal peptidyl transferase has a specificity for L-a-amino acids, which may account for the use of a single optical isomer in protein amino acids. The chemical basis for the selection of a-amino acids can be understood by considering the deleterious properties that beta, theta, and gamma-amino acids give to peptides or have for protein synthesis
 
Melissa Ilardo: (2015): Comparing the encoded amino acid alphabet to random sets of amino acids in regards of size, charge, and hydrophobicity, to the standard amino acid alphabet, only six sets with better coverage out of the 10^8 possibilities tested were detected. Sets that cover chemistry space better than the genetically encoded alphabet are extremely rare and energetically costly. The amino acids used for constructing coded proteins may represent a largely global optimum, such that any aqueous biochemistry would use a very similar set. That's pretty impressive and remarkable. That means, that only one in 16 million sets is better suited for the task.

Selecting the proteome for the first organism
David T.F Dryden (2008): A typical estimate of the size of sequence space is 20^100 (approx. 10^130) for a protein of 100 amino acids in which any of the normally occurring 20 amino acids can be found. This number is indeed gigantic.

Connecting all 1,350 proteins ( each, average 300 amino acids in length)  in the right, functional order is: In each of the 1350 positions, you can choose amongst 1350 different proteins, and only one is functional. that gives odds in the order of 10^182,500

In drug design, researchers employ systematic search, utilizing different techniques, using targets ( or goals) as a guide, integrating techniques, implementing search strategies, modeling, evaluating, enumerating, and implementing efficient methods of search. Hume: "Since the effects resemble each other, we are led to infer, by all the rules of analogy, that the causes also resemble; and that the Author of nature is somewhat similar to the mind of man; though possesses of much large faculties, proportioned to the grandeur of the work executed. By this argument a posteriori, and by this argument alone, do we prove at once the existence of a Deity, and his similarity to human mind and intelligence. ..." If humans employ their mind, and various techniques resorting and using their intelligence, to sort out which molecules in a vast "chemical space" bear the desired function, the same must apply to the quartet of macromolecules used in life, and the genome, proteome, and interactome, necessary to create self-replicating, living cells.

Image source: Autocatalytic chemical networks at the origin of metabolism
https://royalsocietypublishing.org/doi/10.1098/rspb.2019.2377#:~:text=RAFs%20are%20consistent%20with%20an,early%20Earth%20chemistry%20and%20life.

Biochemical fine-tuning - essential for life Core-m10

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The First Cell: Elucidating the Gap Between Non-Life and Life

The Quantum Leap to Life: Unraveling the Mysteries of Biogenesis

Introduction

The origin of life remains one of the most profound and elusive questions in science. For nearly a century, researchers have sought to unravel the mystery of how inanimate matter transformed into the first living cell. 

Eugene V. Koonin: The Logic of Chance (2012): Despite many interesting results to its credit, when judged by the straightforward criterion of reaching (or even approaching) the ultimate goal, the origin of life field is a failure—we still do not have even a plausible coherent model, let alone a validated scenario, for the emergence of life on Earth. Certainly, this is due not to a lack of experimental and theoretical effort, but to the extraordinary intrinsic difficulty and complexity of the problem. A succession of exceedingly unlikely steps is essential for the origin of life, from the synthesis and accumulation of nucleotides to the origin of translation; through the multiplication of probabilities, these make the final outcome seem almost like a miracle.1

This quest involves chemistry, biology, and physics, pushing the boundaries of our understanding and challenging our preconceptions about the nature of life itself. Throughout this period, we have witnessed a consistent commitment to finding naturalistic explanations for life's origin. Researchers have moved from broad concepts to more specific chemical scenarios, acknowledging the challenges while remaining dedicated to scientific explanations. This progression reflects the scientific method in action: starting with hypotheses, conducting experiments, refining ideas, and gradually building a more comprehensive understanding. However, as our knowledge of life's complexity has grown, so too has the challenge of explaining its emergence. Each new discovery seems to widen the gap between our understanding of chemistry and our grasp of biology's complex systems. The transition from non-life to life, once thought to be a small step, now appears to be a quantum leap of staggering proportions.

Here, we explore the current state of origin-of-life research, examining the paradoxical situation we find ourselves in: armed with more knowledge than ever before, yet seemingly further from a complete explanation of life's beginnings. We will go into the challenges that have emerged, the new questions that have arisen, and the potential pathways forward in this critical area of scientific inquiry. As we embark on this journey, we will confront the possibility that the origin of life may require us to rethink our fundamental assumptions about the nature of matter, energy, and information. We will explore cutting-edge theories and experiments that seek to bridge the chasm between non-life and life, and consider the implications of this research for our understanding of life, the universe, and our place within it.

Throughout time, we see a consistent commitment to finding naturalistic explanations for life's origin. Researchers have moved from broad concepts (Oparin, Haldane) to more specific chemical scenarios (Miller), acknowledging the challenges (Crick) while remaining committed to scientific explanations (Dawkins, Szostak, Lane).

Alexander Oparin (1930s): The first stage in the origin of life was the formation of simple organic compounds from the atmospheric gases.

J.B.S. Haldane (1940s): The origin of life was essentially a chemical process.

Stanley Miller (1950s): The idea that the organic compounds that serve as the basis of life were formed when the primitive Earth had a reducing atmosphere is commonly accepted today.

Adler (1959) in the book " How life began" 1  wrote: The development of life appears as something that just happened, without any design or purpose. It started from the accidental mixing and combining of chemicals in the primitive sea. But the direction of development it took was not all accidental. It was influenced by the natural preferences the chemical elements have for each other. It was built on the basis of carbon's ability to form long-chain compounds. In the later stages of chemical evolution, it was also directed by the effects of natural selection. The rule of survival of the fittest guided evolution toward the development of more complicated and more efficient organisms, and finally toward the emergence of intelligent beings.

Francis Crick (1960s): The origin of life appears at the moment to be almost a miracle, so many are the conditions which would have had to have been satisfied to get it going.

Richard Dawkins (1980s): The illusion of design is a trap that has ensnared many people. The beauty of Darwin's theory is that it explains the illusion of design without requiring a designer.

In 1996, Lynn Margulis was interviewed by John Horgan, and it was published in Horgan's book: The End of Science 2 The smallest bacterium, she ( Margulis ) noted, “is so much more like people than Stanley Miller’s mixtures of chemicals, because it already has these system properties.  So to go from a bacterium to people is less of a step than to go from a mixture of amino acids to that bacterium.”

Today, we find ourselves even further from solving this puzzle than we were 70 years ago, when abiogenesis research began in earnest with the discovery of DNA's structure by Watson and Crick and the Miller-Urey experiment synthesizing amino acids under simulated early Earth conditions. Despite our increasing understanding of life's complex machinery, the fundamental question of how inanimate matter transformed into the first living cell remains more elusive than ever. This book elucidates the current state of origin-of-life research, exploring the widening chasm between our knowledge of life's complexity and our ability to explain its emergence through natural processes. It examines the challenges, paradoxes, and potential new directions in the quest to unravel one of science's most enduring enigmas: the nature of life's quantum leap from chemistry to biology.

Jack Szostak (2000s): The origin of life is a problem in chemistry that we hope to solve in the next few decades.

Nick Lane (2010s): Life is not a miracle, but a natural consequence of the laws of physics and chemistry.

This progression reflects the scientific method in action: starting with hypotheses, conducting experiments, refining ideas, and gradually building a more comprehensive understanding. While the origin of life remains an open question, these researchers share a common belief that the answer lies within the realm of natural processes, governed by chemistry and physics. This is paradoxa, because, rather than bringing us closer to understanding how the transition from non-life to life could have occurred by natural means, these discoveries have paradoxically widened the gaps in our knowledge. 

The Journey from Non-Life to Life: A Scientific Perspective from Half a Century Ago

Starting about 100 years ago, scientists and researchers envisioned the transition from non-living matter to life as follows: Scientists studying life's beginnings started in the attempt of explaining how natural processes could have transformed simple carbon and nitrogen compounds in ancient oceans into living entities. Pioneers like A. I. Oparin (1924) and J. B. S. Haldane (1929) were the first to seriously tackle this enigma. Their work inspired numerous scientists to conduct laboratory experiments and formulate theories based on their findings. Notable contributors included J. D. Bernal, M. Calvin, S. W. Fox, S. L. Miller, L. E. Orgel, J. Oró, C. A. Ponnamperuma, and H. C. Urey. Researchers proposed that the chemical evolution leading to life occurred in three distinct phases. The first phase involved the creation of simple building blocks monomers. The second phase saw the development of complex molecules or polymers. The final phase encompassed the organization of these polymers into self-regulating systems that we recognize as living cells. Scientists theorized that the formation of amino acids and nitrogen bases required energy. They identified several potential energy sources present on Earth over three billion years ago, including lightning, radiation from radioactive elements and cosmic rays, solar ultraviolet rays, meteorite impacts, and heat. In 1953, S. L. Miller conducted a groundbreaking experiment. He created a mixture simulating Earth's early atmosphere and subjected it to electrical discharges, mimicking lightning. This process successfully produced amino acids, demonstrating that primordial energy sources could have generated these crucial building blocks. Subsequent experiments showed that all theorized energy sources from the early Earth could potentially form amino acids in both atmospheric and oceanic conditions. Additionally, chemical analysis of meteorites suggested that amino acids might have formed in interplanetary dust and arrived on Earth via meteorite impacts. Researchers proposed various mechanisms for concentrating monomers to facilitate their combination into biologically significant polymers. Oparin suggested coacervate formation, while Bernal proposed adsorption onto clay, which then catalyzed monomer joining. Fox hypothesized concentration through evaporation in tidal pools, followed by heat-induced joining. Calvin and Oró suggested that certain cyanogen-derived compounds could enable direct polymer formation in seawater without prior concentration. Laboratory experiments confirmed the viability of all these proposed methods, indicating multiple potential pathways for natural processes to combine amino acids into protein-like chains and to form nucleic acids from nitrogen bases, sugars, and phosphates. Researchers also noted that spontaneous amino acid combinations in laboratories showed preferences for certain pairings, mirroring patterns observed in cellular proteins. This similarity suggested that protein molecule amino acid sequences evolved from natural affinities between amino acids. Scientists theorized that the accidental joining of metal molecules (like iron) to amino acids might have initiated enzyme evolution. They also proposed that the combination of phosphates with nitrogen bases and sugars could have led to ATP formation. Additionally, experiments showed that phospholipids and proteins could spontaneously form sheets resembling cell membranes under specific conditions.

This final phase remained the most mysterious, with limited experimental evidence to support theories. Scientists were unsure whether it occurred after or concurrently with polymer formation. Despite the lack of concrete evidence, these theories were valuable in guiding future experiments and refining hypotheses. Oparin's coacervate theory provided the most detailed scenario for cell evolution. He envisioned the primordial sea as a vast "organic soup" where increasingly complex molecules formed through natural processes. Amino acids, capable of diverse combinations, produced a variety of protein molecules large enough to form colloidal particles, gradually transforming the sea into a colloidal solution. These colloidal particles sometimes formed clusters known as coacervates, separated from the surrounding sea by a thin water molecule skin. This development was seen as a crucial step towards the formation of protoplasm. The coacervate's skin acted as both a barrier and a passageway, allowing a steady flow of molecules in and out of the cluster. Over time, some coacervates developed a balance between breakdown and buildup processes, leading to stability and growth. This balance was seen as a precursor to cellular metabolism. The need for a continuous supply of molecules for the building-up process was likened to the "feeding" behavior of living organisms. Scientists proposed that a form of natural selection occurred among these coacervates, with the more stable ones persisting and evolving. They suggested that some coacervates developed catalytic processes that enhanced their efficiency, leading to the eventual evolution of enzyme systems. As organic compounds in the sea were increasingly absorbed by coacervates, competition for resources intensified. This "struggle for existence" was thought to have accelerated the process of natural selection, favoring coacervates with the most stable metabolism, efficient enzyme systems, and effective reproduction mechanisms. Through countless small changes over millions of years, researchers believed that coacervates eventually developed into the first primitive living organisms. These early life forms were imagined to be even simpler than bacteria or blue-green algae, obtaining energy through anaerobic fermentation processes. Despite their simplicity, scientists speculated that these organisms must have possessed some mechanism for energy storage and transfer, possibly involving ATP or a similar compound. This narrative represents the scientific community's best understanding of life's origins up to approximately half a century ago. It laid the groundwork for further research and continues to influence our quest to unravel the mysteries of life's beginnings.

The scientific understanding of life's origins has evolved significantly over the past half-century. In the 1980s, the discovery of ribozymes (RNA molecules with catalytic properties) by Thomas Cech and Sidney Altman led to the formulation of the RNA World hypothesis. This theory proposed that RNA could have served as both a genetic material and a catalyst in early life forms, potentially bridging the gap between prebiotic chemistry and cellular life. Researchers like Stanley Miller continued to refine prebiotic synthesis experiments, exploring a wider range of potential early Earth conditions. The discovery of extraterrestrial organic compounds in meteorites and comets strengthened the idea that some of life's building blocks might have an cosmic origin. The field of systems chemistry emerged, focusing on how complex networks of chemical reactions could lead to self-sustaining, self-replicating systems. Jack Szostak and others made significant progress in creating socalled protocells - simple membrane-enclosed structures capable of growth and division. Hydrothermal vents, particularly alkaline vents, gained attention as potential cradles of life. Researchers like Nick Lane proposed that the chemical and energy gradients in these environments could have driven the formation of early metabolic processes.

Current Understanding

1. Multiple Hypotheses: There's no single, universally accepted theory for the origin of life. Instead, several competing hypotheses exist, including the RNA World, the Iron-Sulfur World, and the Lipid World.
2. Complexity of Early Life: We now recognize that even the simplest forms of life are incredibly complex. The gap between prebiotic chemistry and the first cell appears larger than previously thought.
3. Information Problem: A key challenge is explaining how complex, information-rich polymers like RNA or DNA could have arisen and replicated before the existence of enzymes.
4. Metabolism-First vs. Replication-First: Debates continue over whether metabolism or replication came first in the origin of life, with some researchers proposing that both might have co-evolved.
5. Role of Compartmentalization: The importance of creating bounded systems (like protocells) for concentrating reactants and enabling evolution is increasingly recognized.
6. Expanded Prebiotic Inventory: Our understanding of the chemical diversity possible under prebiotic conditions has grown, including the potential for more complex organic synthesis.
7. Importance of Energy Flows: There's increased focus on how energy fluxes and disequilibrium could have driven the emergence of life.
8. Synthetic Biology Approaches: Researchers are using synthetic biology techniques to reconstruct possible early biological systems, providing new insights into life's origins.
9. Exoplanet Studies: The discovery of numerous exoplanets has broadened our perspective on the potential conditions for life's emergence.

Despite these advancements, the origin of life remains one of science's greatest unsolved mysteries. The complexity of even the simplest living systems and the vast timescales involved continue to challenge our understanding. Current research is increasingly interdisciplinary, drawing on fields ranging from astronomy to quantum physics in the quest to understand how life began.

The  Journey from Prebiotic Chemicals to the Progenote,  to Modern Life Domains

The list shows the progression from the simplest level of organization (atoms) to the most complex (ecosystems), representing a bottom-up approach to understanding biological organization and complexity. It is a very general scheme, intended to show merely the increasing organizational complexity of several processes. Although eight steps are shown, leading from atoms to ecosystems, there is one step that far outweighs the others in enormity: the step from macromolecules to cells. All the other steps can be accounted for on theoretical grounds—if not correctly, at least elegantly. However, the macromolecule-to-cell transition is a jump of fantastic dimensions, which lies beyond the range of testable hypotheses. In this area all is conjecture. The available facts do not provide a basis for postulating that cells arose on this planet. This is not to say that some parachemical forces were at work. We wish to point out the fact that there is no scientific evidence. The physicist had learned to avoid trying to specify when time began and when the matter was created, except within the framework of frank speculation. The origin of the precursor cell appears to fall into the same category of unknowables. It is an area with fascinating conceptual changes, but at present, and perhaps forever, the facts cannot be known. To postulate that life arose elsewhere in the universe and was then brought to earth by some means would be merely begging the question; we must still answer how life arose wherever it may have done so originally.

Stages of Bottom-Up Development

1. Atoms Fundamental building blocks of matter.
2. Prebiotic chemical synthesis Formation of simple organic molecules from inorganic precursors in early Earth conditions.
3. Molecular self-assembly Creation of more complex structures like protocells through spontaneous organization of molecules.
4. RNA World Development of self-replicating RNA molecules capable of storing information and catalyzing reactions.
5. RNA-Protein World Emergence of primitive translation systems, allowing RNA to guide protein synthesis.
6. DNA-RNA-Protein World Transition to DNA as the primary genetic material, with RNA as an intermediate and proteins as functional molecules.
7. Proto-cell formation Development of lipid membranes and basic metabolic processes, creating the first cell-like structures.
8. LUCA (Last Universal Common Ancestor) Emergence of a self-replicating organism with DNA, RNA, and proteins, from which all current life descended.
9. Individuals Distinct, self-contained living entities capable of independent existence.
10. Populations Groups of individuals of the same species living in a particular area.
11. Species, communities Interbreeding groups and diverse assemblages of different species interacting in an ecosystem.
12. Ecosystems Complex networks of living organisms interacting with their physical environment.


Biochemical fine-tuning - essential for life Rsta2011
A (conjectured) brief sketch of the history of life. At present, life is divided into three domains: Bacteria, Archaea and Eukaryota. Following the lineages of the three domains backward in time (solid lines), we find that they coalesce into the Last Universal Common Ancestor (LUCA), approximately 3.8 Gya. The dashed red line indicates the point in time where it is thought that the Darwinian transition occurred: before that, life was evolving in a communal way (progenote); after the Darwinian transition, life evolved as described by the Modern Synthesis. 1

Last Universal Common Ancestor (LUCA) vs First Universal Common Ancestor (FUCA)

LUCA (Last Universal Common Ancestor)
Definition: Most recent common ancestor of all current life
Timeframe: ~3.5-3.8 billion years ago
Characteristics:
Simple, single-celled organism
DNA-based genetic code
Ribosomes for protein synthesis
Basic cellular machinery and metabolism
Cell membrane

FUCA (First Universal Common Ancestor)
Definition: Hypothetical first common ancestor of all life
Timeframe: Earlier than LUCA, possibly >3.8 billion years ago
Characteristics (highly speculative):
Primitive genetic material (possibly RNA)
Basic metabolic processes
Rudimentary cell-like structures

Key Differences
Complexity: LUCA more complex than FUCA
Genetic Material: LUCA likely DNA-based, FUCA possibly RNA-based
Evolutionary Stage: LUCA later stage, FUCA earlier stage
Evidence: More indirect evidence for LUCA, FUCA largely speculative

Why FUCA is Problematic in Origin of Life Studies

In Origin of Life research, focusing on FUCA presents significant challenges:

Lack of Evidence: There is virtually no direct evidence about the nature of FUCA due to its extreme antiquity.
High Speculation: Any attempt to define FUCA relies heavily on speculation rather than scientific data. The period between the origin of life and LUCA makes it difficult to pinpoint a single "first" ancestor.
Definition Issues: The boundary between non-life and life is blurry, making it challenging to define what qualifies as the "first" living entity.
Methodological Limitations: Current scientific methods are not capable of providing concrete information about life forms from such an early period.

Advantages of Focusing on LUCA in Bottom-Up Research

More Tangible Evidence: Comparative genomics provides indirect but substantial evidence about LUCA's nature.
Clearer Definition: LUCA represents a more defined point in evolutionary history.
Practical Research Target: Studying LUCA allows for more concrete hypotheses and experimental designs.
Bridge to Modern Life: LUCA serves as a crucial link between early life and the diversity we see today.
Consensus in Scientific Community: There's broader agreement on LUCA's existence and general characteristics.

While the concept of FUCA is intriguing, its highly speculative nature makes it less practical for scientific investigation. Focusing on LUCA as a threshold for investigation in bottom-up research provides a more solid foundation for understanding the origins and early evolution of life on Earth.

Broader Stages of Bottom-Up Development


Biochemical fine-tuning - essential for life Semfff12


This diagram presents a hypothetical timeline for the emergence of life, illustrating key stages in the transition from prebiotic chemistry to biological complexity. The left-hand sequence depicts a possible order of events, beginning with the chemical synthesis of organic compounds and progressing through increasingly complex stages. Notably, this model proposes the formation of RNA prior to encapsulation in vesicles, though it's acknowledged that the reverse sequence is equally plausible and widely debated among scientists. The right side of the diagram visualizes a critical concept in origin-of-life studies: the "bottleneck" through which chemical evolution passed to give rise to biological systems. This narrowing represents the transition from the vast chemical diversity of the primordial Earth to the more specific and uniform biochemistry that characterizes life as we know it. As the process moves through this bottleneck, we see a shift from high chemical diversity to high morphological diversity. The initial stages feature a wide array of chemical possibilities, which gradually converge on the specific set of biomolecules used by life. Simultaneously, this chemical specialization enables the emergence of diverse biological structures and functions. The alignment of the left and right sides of the diagram illustrates how each chemical/biological milestone corresponds to a stage in this narrowing process. Early stages like the synthesis of organic compounds and autocatalytic reactions align with the period of high chemical diversity. Later stages, such as the formation of DNA and the emergence of prokaryotic life, correspond to the expansion of morphological diversity. This model, adapted from work by Preston Cloud (1988), offers a conceptual framework. It emphasizes both the sequential nature of life's emergence and the fundamental shift from chemical to biological complexity that characterizes this process. 4

1. Chemical synthesis of organic compounds: Simple inorganic molecules would combine to form more complex organic compounds under various energy inputs from the primordial Earth.
2. Autocatalytic reaction sets: These organic compounds are proposed to form self-replicating systems, possibly within primitive vesicles, increasing the complexity of the prebiotic world.
3. Synthesis of heterochiralic nucleotides: The first nucleotides would form, but with mixed chirality.
4. Synthesis of non-chiral PNA or ONA: Precursor molecules to RNA, such as peptide nucleic acids (PNA) or other nucleic acids (ONA), are supposed to emerge without specific chirality.
5. Phase-transition/chiral symmetry breaking: A critical event is proposed to occur, leading to the preference for one chirality over another.
6. Takeover of the medium by chiral nucleotides: The environment would become dominated by nucleotides of a specific chirality.
7. Synthesis of chiral RNA: The formation of RNA molecules with a consistent chirality is thought to mark the transition to a proto-biological world.
8. Encapsulation in vesicles: RNA would become enclosed within lipid vesicles, if this hadn't occurred earlier.
9. Formation of chiral amino acid sets with RNA mediation: RNA is proposed to begin influencing the formation of specific amino acid sequences.
10. Formation of enzymatic proteins: The first functional proteins are thought to emerge, capable of catalyzing specific reactions.
11. First enzyme-mediated cells: Primitive cells with enzymatic capabilities would form, marking the beginning of the first RNA world.
12. Formation of DNA: The transition from RNA to DNA as the primary genetic material is proposed to occur at this stage.
13. Universal cellular ancestor: A common ancestor for all current life would emerge from these early cellular forms.
14. Prokaryotic life (bacteria): The first recognizable cellular life forms, resembling modern bacteria, are supposed to appear.

Throughout this progression, chemical diversity is proposed to narrow through a "bottleneck" phase, representing the transition from the vast chemical possibilities of the prebiotic world to the more specific and uniform chemistry of biological systems. As chemical diversity decreases, morphological diversity would increase, leading to the variety of life forms we see today. Throughout this progression, chemical diversity is proposed to narrow through a "bottleneck" phase, representing the transition from the vast chemical possibilities of the prebiotic world to the more specific and uniform chemistry of biological systems. As chemical diversity decreases, morphological diversity would increase, leading to the variety of life forms we see today. This scenario, while speculative, captures the key transitions from simple chemicals to complex cellular life, highlighting the major milestones in the proposed origin of life as we know it.

1. Prebiotic World

1.1. Chemical synthesis of organic compounds
   - (No specific enzymes at this stage, as these are prebiotic processes)

1.2. Autocatalytic reaction sets
   - (No specific enzymes, but self-replicating molecules emerge)

1.3. Synthesis of heterochiral nucleotides
   - (No specific enzymes, but important for RNA world)

1.4. Synthesis of non-chiral PNA or ONA
   - (Precursors to genetic polymers)

2. RNA World

2.1. Phase-transition/chiral symmetry breaking
2.2. Takeover of the medium by chiral nucleotides
2.3. Synthesis of chiral RNA

3. RNP (Ribonucleoprotein) World

3.1. Formation of chiral amino acid sets with RNA mediation
3.2. Formation of enzymatic proteins

4. Proto-Cellular World

4.1. Encapsulation in vesicles
4.2. First enzyme-mediated cells

5. Early Cellular World

5.1. III. Nucleotide Synthesis and Salvage
5.2. IV. Amino Acid Biosynthesis
5.3. V. Regulatory Enzymes and Proteins in Amino Acid Synthesis
5.4. XIII. Cofactors
5.5. II. Energy Metabolism, Central Carbon Metabolism, and Other Specific Pathways
5.6. XIV. NAD Metabolism
5.7. XII. Fatty Acid and Phospholipid Synthesis in LUCA
5.8. XVI. Membrane Transport Systems
5.9. I. Metal Clusters and Metalloenzymes

6. Complex Cellular Systems

6.1. VI. Translation/Ribosome in the LUCA
6.2. VII. Biosynthesis and Assembly of the Bacterial Ribosome
6.3. VIII. Transcription/Regulation in the LUCA
6.4. XX. RNA Processing and Degradation
6.5. IX. DNA Processing in LUCA
6.6. XII. Formation of DNA

7. Advanced Cellular Functions

7.1. X. Families/Functions Involved in Various Aspects of Cell Division in LUCA
7.2. XI. Peptidoglycan Synthesis
7.3. XV. Reactive Oxygen Species (ROS) Management
7.4. XVII. Protein Folding and Degradation
7.5. XVIII. Stress Response Systems
7.6. XIX. Lipopolysaccharide Synthesis (Gram-negative bacteria)
7.7. XXI. Signal Transduction Systems
7.8. XXII. Autotrophic Processes

8. XXIII. Uncharacterized


1. The Logic of Chance: The Nature and Origin of Biological Evolution Eugene V. Koonin 1

Comprehensive List of Proto-LUCA Enzymes and Proteins

1. Prebiotic world

The chemical synthesis of organic compounds in the prebiotic world is a cornerstone of origin of life research, offering insights into how the building blocks of life may have formed before the emergence of biological systems. This exploration into prebiotic chemistry delves into the various organic molecules, reactions, and processes believed to have been pivotal in Earth's early history. The prebiotic era is said to have begun with simple organic molecules present in the primordial atmosphere and oceans. Compounds such as formaldehyde, hydrogen cyanide, and ammonia would have served as fundamental precursors for more complex biomolecules. From these humble beginnings, a cascade of chemical reactions would have have given rise to the diverse array of organic compounds necessary for life. As we examine the prebiotic synthesis of increasingly complex molecules - amino acids, nucleobases, sugars, and lipid precursors - we begin to see the chemical foundations of life taking shape. Each of these molecular classes plays an indispensable role in modern biological systems, and understanding their abiotic formation is crucial for hypothesizing life's emergence. Key reactions and processes that could have facilitated the formation of these organic compounds span a range of potential prebiotic environments. From atmospheric processes modeled in the famous Miller-Urey experiment to reactions in hydrothermal vents and on mineral surfaces, the possible settings for prebiotic chemistry are diverse. Beyond mere synthesis, other critical aspects of prebiotic chemistry demand attention. Concentration mechanisms that would have accumulated dilute organic compounds into more reaction-favorable conditions are essential to consider. Additionally, the emergence of chirality - a defining feature of biological molecules - presents a considerable puzzle with various proposed solutions. While our understanding of prebiotic organic synthesis has advanced significantly, many aspects remain unsolved. The field continues to evolve as new experimental techniques are developed and our knowledge of early Earth conditions improves. By examining these potential prebiotic syntheses and processes, we gain valuable insight into the chemical foundations that would have preceded and enabled the origin of life. This exploration sets the stage for understanding how more complex biomolecules, including the first enzymes and proteins, would have emerged in the journey towards the supposed  Last Universal Common Ancestor (LUCA) and the remarkable diversity of life we observe today.

1.1. Chemical synthesis of organic compounds

a) Simple organic molecules

1. Formaldehyde (CH2O): A key precursor for more complex organic molecules, including sugars through the formose reaction.
2. Hydrogen cyanide (HCN): Important for the synthesis of amino acids and nucleobases.
3. Ammonia (NH3): A source of nitrogen for amino acids and other biologically important molecules.
4. Methane (CH4): Can serve as a carbon source and participate in various organic reactions.
5. Carbon dioxide (CO2): A carbon source for various organic compounds and important for early metabolic processes.
6. Water (H2O): The universal solvent, crucial for all known life processes.

These molecules are considered "building blocks" of life, as they can react and combine to form more complex organic compounds essential for living systems, such as amino acids, nucleotides, and sugars.

Open questions related to the origin of these organic molecules on prebiotic Earth

1. Formation mechanisms: How exactly were these molecules formed on early Earth? Were they primarily produced through atmospheric reactions, hydrothermal vents, or delivered by comets and meteorites?
2. Concentration and accumulation: How did these simple molecules accumulate in sufficient concentrations to drive more complex chemistry?
3. Energy sources: What were the primary energy sources (e.g., UV radiation, lightning, geothermal heat) driving the formation of these molecules?
4. Environmental conditions: What were the exact atmospheric and oceanic conditions that favored the formation and stability of these molecules?
5. Transition to complexity: How did these simple molecules combine to form more complex organic compounds, and what catalysts or environmental factors facilitated this process?
6. Chirality: How did the homochirality of life (preference for L-amino acids and D-sugars) emerge from these achiral precursors?
7. Temporal sequence: In what order did these molecules appear, and how did their relative abundances change over time?
8. Stability and preservation: How were these molecules protected from degradation in the harsh conditions of early Earth?
9. Local vs. global production: Were these molecules produced uniformly across the planet, or were there specific "hotspots" of organic synthesis?
10. Role of minerals: How did interactions with mineral surfaces influence the formation and reactions of these molecules?

These open questions continue to drive research in the field of prebiotic chemistry and origin of life studies. Scientists use various approaches, including laboratory simulations, theoretical modeling, and analysis of ancient rocks and meteorites, to piece together the puzzle of how these simple organic molecules led to the emergence of life on Earth.

b) Amino acids

Amino acids are organic compounds that serve as the fundamental building blocks of proteins in living systems. These molecules consist of a central carbon atom bonded to an amino group (-NH2), a carboxyl group (-COOH), a hydrogen atom, and a variable side chain (R group) that gives each amino acid its unique properties. In living organisms, amino acids play following essential roles:

1. Protein synthesis: They are the monomers that link together to form the long chains of proteins, which are essential for virtually all biological processes.
2. Metabolic functions: Some amino acids serve as precursors for important biomolecules like neurotransmitters, pigments, and hormones.
3. Energy source: When carbohydrates are scarce, amino acids can be broken down to provide energy.

The importance of amino acids in life cannot be overstated. They are integral to the structure and function of enzymes, which catalyze biochemical reactions. They also contribute to cellular signaling, immune responses, and the transport of key molecules throughout organisms. While there are hundreds of amino acids found in nature, life predominantly uses a set of 20 standard amino acids to build proteins. This specific set is thought to have been evolutionarily selected for its ability to create a diverse array of protein structures and functions while maintaining a balance between complexity and efficiency. These 20 amino acids provide a wide range of chemical properties - including hydrophobic, hydrophilic, acidic, and basic characteristics - allowing for the creation of proteins with highly specialized structures and functions. The reasons for the selection of these particular 20 amino acids are still debated in the scientific community. Hypotheses range from their availability in the prebiotic world to their ability to form a complete and efficient "chemical toolkit" for life. Understanding the origin and selection of these 20 amino acids remains an active area of research in the fields of biochemistry and the origin of life studies.

Biochemical fine-tuning - essential for life Amino_11
Image source: Link 

List of problems associated with prebiotic amino acid formation

1. Precursor availability: Scarcity of fixed nitrogen and carbon sources, reactivity of organosulfur compounds, and instability of ammonia in early Earth conditions.
2. Nitrogen fixation: Abiotic processes like lightning strikes are sporadic and inefficient for consistent nitrogen availability.
3. Carbon sources: Conversion of CO2 or CH4 into reactive organic molecules requires specific conditions and catalysts.
4. Sulfur reduction: Reduction of oxidized sulfur compounds to forms usable in amino acid synthesis is challenging.
5. Ammonia instability: Rapid photochemical dissociation of ammonia under early Earth's UV radiation.
6. Contradictory conditions: Specific requirements for amino acid synthesis often conflict with conditions for precursor stability and reactivity.
7. Thermodynamic barriers: Peptide bond formation faces significant thermodynamic hurdles in aqueous environments.
8. Kinetic barriers: Slow rates of spontaneous peptide bond formation compared to amino acid degradation.
9. Concentration issues: Achieving sufficiently high concentrations of amino acids for peptide formation is problematic.
10. Chirality: Maintaining homochirality necessary for functional peptides is difficult under prebiotic conditions.
11. Hydrolysis: Protecting formed peptides from hydrolysis in aqueous environments is challenging.
12. Sequence specificity: Achieving the specific sequences necessary for functional peptides through random polymerization is highly improbable.
13. Missing amino acids: Eight proteinogenic amino acids have never been observed in prebiotic synthesis experiments.
14. Stability-reactivity paradox: Balancing the stability of amino acids for accumulation with their reactivity for peptide formation.
15. Environmental stability: Maintaining stable conditions (pH, temperature) conducive to both amino acid stability and peptide formation.
16. Energy sources: Sufficient energy for synthesis and concentration processes must be available without destroying formed molecules.
17. Selective activation: Amino acids must be selectively activated to form peptide bonds without undesired side reactions.
18. Catalytic surfaces: The need for specific catalytic surfaces or minerals to facilitate peptide bond formation.
19. Sequential polymerization: Difficulty in achieving the specific sequence of amino acids required for functional peptides.
20. Stable intermediates: Intermediate peptide structures must be stable enough to avoid decomposition.
21. Concentration mechanisms: Efficient mechanisms to concentrate and localize reactants and products are necessary but challenging to achieve.
22. Interfering molecules: Presence of molecules that could disrupt synthesis or polymerization.
23. UV protection: Mechanisms to protect amino acids and peptides from UV radiation damage.
24. Selective accumulation: Preventing the preferential concentration of simpler, competing molecules.
25. Racemization: Rapid racemization of amino acids impedes the formation of homochiral peptides essential for functional biology.
26. Yield inefficiency: Low yields in peptide formation necessitate initial amino acid concentrations orders of magnitude higher than achievable through current methods.
27. Quantitative requirements: Need for concentrations in the millimolar range, far exceeding known prebiotic synthesis capabilities.
28. Mutual exclusivity: Many required conditions for amino acid synthesis and peptide formation are mutually exclusive or contradictory under prebiotic conditions.
29. Timescale issues: Balancing the time required for accumulation with the degradation rates of amino acids and peptides.
30. Complex environment interactions: Difficulty in modeling and understanding the complex interactions between various environmental factors affecting amino acid synthesis and stability.
31. Equilibrium concentrations: Extremely low equilibrium concentrations of even short peptides (e.g., nonapeptides) under prebiotic conditions.
32. Wet-dry cycles: Challenges in maintaining homochirality and preventing hydrolysis during wet-dry cycles in scenarios like the drying lagoon hypothesis.
33. Hydrothermal vent limitations: While providing high temperatures and mineral surfaces, hydrothermal vents also lead to rapid hydrolysis and racemization of peptides.
34. Absence of biological catalysts: Lack of enzymes and other biological catalysts that facilitate amino acid and peptide formation in modern cells.
35. Competing reactions: Presence of competing reactions that may consume amino acid precursors or formed amino acids.
36. Limited prebiotic pathways: Known prebiotic synthesis routes produce only a subset of the necessary amino acids.
37. Concentration gradients: Difficulty in maintaining concentration gradients necessary for certain proposed concentration mechanisms.
38. Mineral surface selectivity: Challenges in achieving selective adsorption of amino acids on mineral surfaces for concentration and catalysis.
39. Chemical complexity: The prebiotic environment likely contained a complex mixture of chemicals, potentially interfering with specific amino acid synthesis pathways.
40. Energetic requirements: High energy requirements for certain steps in amino acid synthesis and peptide formation.
41. Prebiotic atmosphere: Uncertainty about the exact composition of the early Earth's atmosphere, affecting assumptions about available precursors.
42. Water activity: High water activity can promote hydrolysis, making it difficult to maintain stable peptides.
43. Oxidative stress: Potential for oxidative damage to amino acids and peptides in the presence of reactive oxygen species.
44. Geochemical diversity: Variability in local geochemical conditions could affect the consistency of amino acid synthesis.
45. Volcanic influences: Volcanic activity could introduce both beneficial and harmful compounds, affecting amino acid formation stability.

List of problems associated with amino acids from space

1. Limited quantities: Amino acids found in meteorites are present in very small amounts, insufficient for initiating life processes.
2. Incomplete set: Not all 20 proteinogenic amino acids have been detected in meteorites or space, leaving gaps in the set required for life.
3. Racemic mixtures: Extraterrestrial amino acids are typically racemic, while life uses only L-amino acids. No known prebiotic mechanism exists for selecting one enantiomer.
4. Survival issues: Many amino acids would likely be destroyed during atmospheric entry and impact, reducing the available quantity.
5. Dilution problem: Any surviving amino acids would be widely dispersed and diluted in Earth's oceans, making concentration difficult.
6. Contamination concerns: Terrestrial contamination of meteorite samples makes it challenging to conclusively prove the extraterrestrial origin of some detected amino acids.
7. Temporal mismatch: Sporadic delivery of amino acids via meteorites doesn't align with the need for a consistent, concentrated supply for prebiotic synthesis.
8. Chemical context: Meteorites contain complex mixtures of organic compounds that could interfere with or outcompete amino acids in further reactions.
9. Lack of directed synthesis: Even if amino acids were available, there's no known prebiotic mechanism to selectively combine them into functional peptides or proteins.
10. Stability in new environment: Amino acids delivered from space would face the same stability issues on early Earth as terrestrially synthesized ones, including rapid degradation.
11. Energy barriers: The presence of amino acids doesn't solve the thermodynamic and kinetic barriers to peptide bond formation in aqueous environments.
12. Specificity problem: Extraterrestrial sources provide no mechanism for the specific sequences required for functional proteins.
13. Competing reactions: In a prebiotic environment, many other reactions would compete with peptide formation, potentially degrading or altering the amino acids.
14. Lack of protective mechanisms: Unlike in living systems, there would be no cellular mechanisms to protect amino acids or peptides from degradation.
15. Integration challenge: Even if amino acids were available, incorporating them into a self-replicating system capable of evolution remains unexplained.

c) Nucleobases

Nucleobases are fundamental components of nucleic acids, playing a crucial role in the storage and transmission of genetic information in all known forms of life. These organic molecules are the primary units of the genetic code, forming the basis of DNA and RNA.

The four nucleobases listed - Adenine, Guanine, Cytosine, and Uracil - are essential to life as we know it:

1. Adenine (A) and Guanine (G) are purines, consisting of two fused rings.
2. Cytosine (C) and Uracil (U) are pyrimidines, with a single-ring structure.

In DNA, Thymine takes the place of Uracil, while RNA uses Uracil instead of Thymine. These bases pair specifically: A with T (or U in RNA), and C with G, forming the rungs of the DNA/RNA ladder.

The importance of nucleobases in living systems cannot be overstated:

1. Genetic information storage: They encode the instructions for building and operating all living organisms.
2. Protein synthesis: They are crucial in the process of transcription and translation, allowing cells to produce proteins based on genetic instructions.
3. Energy transfer: Some nucleobases, particularly Adenine, are components of energy-carrying molecules like ATP.
4. Cellular signaling: They play roles in various signaling pathways within cells.

The presence of these specific nucleobases in life is a subject of ongoing research and debate in origin of life studies. They are used in life due to their stability, their ability to form complementary base pairs, or their availability in the prebiotic environment.  Understanding the prebiotic synthesis and selection of these nucleobases is crucial for unraveling how the first self-replicating molecules may have formed, potentially leading to the emergence of life. This area of study continues to be at the forefront of research into life's origins, with implications ranging from astrobiology to synthetic biology.

Biochemical fine-tuning - essential for life Nucleo13
Source: Wikipedia



Last edited by Otangelo on Mon 5 Aug 2024 - 13:42; edited 1 time in total

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Challenges in Prebiotic Nucleobase Synthesis

1. Complexity: Nucleobase synthesis involves extremely complex chemical processes, challenging to recreate under prebiotic conditions.
2. Specific base synthesis: Certain bases like cytosine and guanine have proven particularly challenging to synthesize under prebiotic conditions.
3. Stability issues: Nucleobases have limited stability under prebiotic conditions, with short half-lives at relevant temperatures.
4. Cytosine synthesis: The prebiotic synthesis of cytosine has proven particularly challenging, with no known successful prebiotic route.
5. Guanine formation: The origin of guanine bases has been a particular challenge in prebiotic chemistry.
6. Adenine synthesis: Adenine synthesis requires unreasonably high hydrogen cyanide concentrations and is prone to rapid deamination.
7. Uracil stability: Uracil has a short half-life at relevant temperatures, making its accumulation in prebiotic environments problematic.
8. Nucleobase tautomerism: Controlling the tautomeric forms of nucleobases to ensure proper base pairing is challenging without biological regulation.
9. Purity of precursors: Prebiotic environments likely contained impure, contaminated chemical pools, unlike the pure reagents used in laboratory synthesis.
10. Concentration problem: Achieving sufficient concentrations of precursors for nucleobase formation is difficult in dilute prebiotic environments.
11. Energy sources: Identifying plausible prebiotic energy sources to drive unfavorable reactions in nucleobase synthesis is challenging.
12. Side reactions: Preventing or controlling unwanted side reactions that could interfere with nucleobase synthesis is difficult in a prebiotic setting.
13. Thermodynamic challenges: Many key reactions in nucleobase synthesis are energetically unfavorable under prebiotic conditions.
14. Environmental conditions: Nucleobase synthesis requires specific conditions (temperature, pH, atmosphere) that may not have been widely available on early Earth.
15. Water paradox: Water is necessary for many reactions but also causes rapid degradation of nucleobases and their precursors.
16. Isomeric configuration: Achieving the correct isomeric configuration of nucleobases is crucial for Watson-Crick base pairing, but difficult to control in prebiotic conditions.
17. Tautomeric equilibria: The precise tautomeric equilibria of nucleobases, essential for correct base pairing, are highly sensitive to environmental conditions.
18. Stereochemistry: Controlling the stereochemistry of sugar components in nucleotides to ensure proper base pairing is challenging without enzymatic guidance.
19. Chiral selection: Explaining the origin of homochirality in nucleotides, necessary for proper base pairing, remains a significant challenge.
20. Bond energies: The fine-tuning of bond energies, particularly in carbon-oxygen double bonds, is crucial for the stability of Watson-Crick base pairs.
21. Hydrogen bonding specificity: Achieving the precise hydrogen bonding patterns required for Watson-Crick base pairing is difficult without biological regulation.
22. Alternative base pairs: Preventing the formation of stable alternative base pairs that could interfere with Watson-Crick pairing is problematic in prebiotic settings.
23. Backbone chemistry: Developing a prebiotic route to the specific sugar-phosphate backbone required for proper base pairing is challenging.
24. Base stacking: Achieving the correct base stacking interactions, which contribute to the stability of the double helix, is difficult to explain prebiotically.
25. Nucleobase analogs: Explaining why nature selected the specific set of nucleobases capable of Watson-Crick pairing from numerous possible analogs is problematic.

Challenges in Prebiotic Nucleobase Synthesis - Addressing Extraterrestrial Sources

The discovery of organic compounds, including nucleobases, in extraterrestrial environments has been one of the most exciting developments in the field of astrobiology and origin of life studies. Nucleobases, the fundamental building blocks of RNA and DNA, have been detected in various cosmic settings, including interstellar space, comets, and meteorites that have fallen to Earth. In 1969, the Murchison meteorite, which fell in Australia, became a landmark in this area of research. Analysis of this carbonaceous chondrite revealed the presence of various organic compounds, including purine and pyrimidine bases. Since then, numerous studies have confirmed the presence of nucleobases in other meteorites, such as the Tagish Lake meteorite and the Antarctic meteorites. Furthermore, space-based observations and laboratory simulations of interstellar ice analogues have suggested that nucleobases could form in the harsh conditions of space. These findings have led some researchers to propose that the essential ingredients for life might have been delivered to early Earth through extraterrestrial sources, potentially jumpstarting the emergence of life. This scenario, often referred to as panspermia or exogenesis, has gained attention as a potential solution to some of the challenges faced in explaining the prebiotic synthesis of these crucial biomolecules on Earth. However, while the presence of nucleobases in space and meteorites is intriguing, it introduces its own set of challenges and does not necessarily solve the fundamental problems of prebiotic nucleobase availability and subsequent RNA or DNA formation. The following points outline why the extraterrestrial source of nucleobases, despite its initial promise, does not fully address the challenges in prebiotic nucleobase synthesis:

6. Limited quantities:
a) Nucleobases found in meteorites are present in very small amounts, often requiring acid hydrolysis for detection.
b) The concentrations are far too low to provide sufficient material for prebiotic synthesis of RNA or DNA.

7. Contamination concerns:
a) There's always a risk of terrestrial contamination in meteorite samples.
b) This makes it difficult to conclusively prove the extraterrestrial origin of detected nucleobases.

8. Incomplete set:
a) Not all necessary nucleobases have been found in meteorites or space.
b) Notably, cytosine, a crucial component of both RNA and DNA, has not been detected in meteorites.

9. Delivery and survival issues:
a) Even if nucleobases were present in meteorites, they would need to survive the extreme conditions of atmospheric entry and impact.
b) Many would likely be destroyed or altered during this process.

10. Dilution problem:
a) Any nucleobases delivered by meteorites would be widely dispersed and diluted in Earth's oceans or bodies of water.
b) Concentrating them to levels necessary for further reactions would be extremely challenging.

11. Chirality issue:
a) Extraterrestrial nucleobases would likely be a racemic mixture.
b) Life uses only specific enantiomers, and there's no known prebiotic mechanism for selecting these.

12. Lack of directed synthesis:
a) Even if nucleobases were available, there's no known prebiotic mechanism to selectively combine them with sugars and phosphates to form nucleotides.
b) The presence of nucleobases alone does not solve the problem of nucleotide or polynucleotide formation.

13. Temporal mismatch:
a) The delivery of nucleobases via meteorites would be sporadic and spread over long periods.
b) This doesn't align with the need for a consistent, concentrated supply for prebiotic synthesis.

14. Chemical context:
a) Meteorites contain a complex mixture of organic compounds, not just nucleobases.
b) Many of these compounds could interfere with or outcompete nucleobases in further reactions.

15. Stability in new environment:
a) Even if nucleobases survived delivery, they would face the same stability issues on early Earth as terrestrially synthesized ones.
b) Rapid degradation would still be a significant problem.

These points illustrate that while the discovery of nucleobases in meteorites and space is interesting, it does not resolve the fundamental challenges of prebiotic nucleobase synthesis and subsequent formation of nucleotides and polynucleotides. The problems of concentration, selective reactions, and stability remain significant hurdles in scenarios involving extraterrestrial sources of nucleobases.

d) Sugars

Sugars play crucial roles in the chemistry of life, particularly in the formation of nucleic acids and energy metabolism. For the origin of life, certain sugars are especially significant due to their involvement in the formation of RNA and DNA. The key sugars essential for the origin of life are:

1. Ribose: A five-carbon sugar that forms the backbone of RNA. It's critical for:
   Genetic information: As part of RNA, it's crucial for the RNA World hypothesis, where RNA may have been the first genetic material.
   Prebiotic chemistry: Its formation under prebiotic conditions is a key area of study in origin of life research.

2. Deoxyribose: A modified form of ribose that lacks one oxygen atom. It's vital for:
   DNA structure: Forms the sugar-phosphate backbone of DNA, which eventually became the primary carrier of genetic information.
   Evolutionary transition: Its emergence may represent a critical step in the evolution of genetic systems.

3. Glucose: While not directly involved in nucleic acid formation, glucose is significant for:
   Energy source: Potentially one of the earliest energy sources for primitive metabolic systems.
   Precursor molecule: Can serve as a starting point for the synthesis of other important biological molecules, including ribose.

These sugars are fundamental to the origin of life:

1. RNA and DNA formation: Ribose and deoxyribose are essential components of RNA and DNA respectively, which are central to genetic information storage and transmission.
2. Energy storage and transfer: Sugars like glucose could have served as early energy sources in prebiotic chemical systems.
3. Prebiotic synthesis: The formation of these sugars under prebiotic conditions is a critical area of study in origin of life research.
4. Chirality: The specific stereochemistry of these sugars is crucial for the function of nucleic acids, presenting challenges and clues for understanding life's origins.

Understanding the prebiotic synthesis and selection of these specific sugars is crucial for unraveling how the first self-replicating molecules may have formed. This area of study continues to be at the forefront of research into life's origins, with implications for astrobiology and our understanding of what constitutes the minimum requirements for life.

Challenges in Prebiotic Sugar Synthesis

You're absolutely right, and I apologize for not providing a more comprehensive explanation earlier. Let's expand on this point and add more details about the challenges associated with the formose reaction and ribose synthesis:

Challenges in Prebiotic Sugar Synthesis - Expanded

1. Complexity of the formose reaction:
   a) The reaction is very complex and depends on the presence of a suitable inorganic catalyst.
   b) It produces over 50 different sugar products, with ribose being only a minor component.
   c) There is no known prebiotic mechanism to selectively isolate ribose from this complex mixture.
   d) Many of the byproducts are not used in life, creating a "chemical chaos" problem.

2. Ribose stability and degradation:
   a) At room temperature (25°C), ribose has a half-life of only about 300 days in neutral solution.
   b) At higher temperatures, typical of some proposed prebiotic scenarios:
      - At 100°C, the half-life of ribose is reduced to about 73 minutes.
      - At 150°C, it degrades even faster, with a half-life of just a few minutes.
   c) This rapid degradation makes it extremely difficult for ribose to accumulate in significant quantities.

3. Concentration problem:
   a) The formose reaction typically produces ribose in very low yields (often less than 1%).
   b) Given the rapid degradation, concentrating ribose to levels necessary for further reactions would be extremely challenging.

4. Chirality issue:
   a) The formose reaction produces a racemic mixture of sugars.
   b) Life uses only D-ribose, and there's no known prebiotic mechanism for selecting this specific enantiomer.

5. Catalytic requirements:
   a) The formose reaction requires specific catalysts (like calcium hydroxide) to proceed efficiently.
   b) The availability and concentration of these catalysts in prebiotic environments is questionable.

6. pH sensitivity:
   a) The formose reaction is highly sensitive to pH, with optimal conditions around pH 11-12.
   b) Such alkaline conditions are rare in natural environments and can be detrimental to other prebiotic processes.

7. Competing reactions:
   a) In a prebiotic environment, many other reactions would compete for the same starting materials (formaldehyde and glycolaldehyde).
   b) These competing reactions could potentially outpace ribose formation.

8. Crossover problem:
   a) The formose reaction can lead to the formation of branched and cyclic sugars.
   b) These non-linear products are not useful for nucleotide synthesis and further complicate the mixture.

9. Formaldehyde availability:
   a) The formose reaction requires a steady supply of formaldehyde.
   b) Maintaining sufficient formaldehyde concentrations in a prebiotic environment is problematic due to its reactivity and volatility.

10. Interference with other prebiotic processes:
    a) The conditions and reactants required for the formose reaction may interfere with other crucial prebiotic processes, such as amino acid or nucleobase formation.

11. Lack of selectivity in further reactions:
    a) Even if ribose were successfully synthesized and isolated, it would need to react selectively with nucleobases to form nucleosides.
    b) There's no known prebiotic mechanism to ensure this selectivity over other sugars present.

12. Energy considerations:
    a) The formose reaction, while autocatalytic, still requires an initial energy input to overcome activation barriers.
    b) Maintaining the reaction over long periods in a prebiotic setting would be energetically challenging.

This list highlights the numerous, interconnected challenges associated with prebiotic ribose synthesis via the formose reaction. The combination of low yield, rapid degradation, lack of selectivity, and the need for specific conditions makes the spontaneous emergence of sufficient quantities of ribose for nucleotide formation highly improbable in a prebiotic setting. These challenges highlight the significant hurdles that would need to be overcome for the prebiotic synthesis of sugars necessary for nucleotide formation. The complexity of these processes and the lack of selective pressures in a prebiotic environment make the spontaneous emergence of these crucial building blocks of life highly improbable without some form of guidance or intervention.




e) Lipid precursors
   Fatty acids
   Glycerol
   Phosphate groups
   Sphingosine bases

f) Key reactions and processes
   Miller-Urey type reactions (electric discharge in reducing atmospheres)
   Formose reaction (for sugar synthesis)
   Strecker synthesis (for amino acid formation)
   HCN polymerization
   Fischer-Tropsch-type synthesis (for lipid precursors)
   Reactions on mineral surfaces (e.g., clay minerals, iron-sulfur minerals)
   Reactions in hydrothermal vents
   Reactions driven by UV radiation
   Prebiotic photochemistry
   Radiolysis of water and organic compounds
   Salt-induced peptide formation
   Oligomerization on mineral surfaces
   Carbonyl sulfide-mediated peptide formation

g) Concentration mechanisms
   Evaporation of primordial pools
   Freeze-thaw cycles
   Adsorption on mineral surfaces
   Concentration in micropores or vesicles
   Thermophoresis in temperature gradients
   Salt-induced phase separation
   Concentration by convection cells in hydrothermal systems

h) Chirality emergence
   Asymmetric photolysis by circularly polarized light
   Asymmetric adsorption on chiral mineral surfaces
   Amplification of slight enantiomeric excesses through autocatalysis
   Chiral symmetry breaking in crystallization processes
   Magnetochiral effect in the presence of magnetic fields
   Parity-violating energy differences between enantiomers
   Enantioselective polymerization on chiral surfaces

This comprehensive list covers the key components and processes involved in the prebiotic synthesis of organic compounds, providing a foundation for the subsequent stages of chemical evolution leading to the emergence of life.



1.2. Autocatalytic reaction sets

1.3. Synthesis of heterochiral nucleotides

1.4. Synthesis of non-chiral PNA or ONA

2. RNA world

2.1. Phase-transition/chiral symmetry breaking

2.2. Takeover of the medium by chiral nucleotides

2.3. Synthesis of chiral RNA

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The Nucleobase Paradox: Chemical Space, Optimization, and the Challenge to Naturalistic Origins - A Comprehensive Analysis

Summary: Nucleobase Fine-Tuning: A Challenge to Naturalistic Origins

The nucleobases found in DNA and RNA represent an extraordinary example of molecular fine-tuning. While chemical space permits over a million possible nucleobase variants, life employs only four specific bases in DNA. These bases exhibit optimal properties for genetic information storage and transmission.

The hydrogen bond strengths between base pairs demonstrate precise calibration. The carbon-oxygen double bond energy measures exactly 30 kcal/mol higher than carbon-carbon or carbon-nitrogen double bonds. This specific energy difference ensures nucleobases exist in their ketone rather than enol forms, enabling Watson-Crick base pairing. Even minor deviations would prevent DNA's double helix formation.

Mathematical analysis reveals the improbability of randomly selecting these optimal configurations. The probability of obtaining a single optimized base equals approximately 10^-9, considering structure selection, correct tautomeric form, and proper spatial arrangement. For all four bases, the probability drops to 10^-36.

Several factors highlight why prebiotic formation appears implausible:

1. No Selection Mechanism
Natural selection requires self-replication, absent in prebiotic conditions. Without reproduction and inheritance, beneficial variations cannot accumulate.

2. Multiple Simultaneous Optimizations
The nucleobases must simultaneously optimize:
- Hydrogen bond strengths
- Base-pairing specificity
- Chemical stability
- Tautomeric preferences
- Backbone compatibility

3. Lack of Foresight
Atoms and molecules cannot anticipate future functional requirements. The nucleobases demonstrate optimization for:
- Information storage
- Enzymatic recognition
- Replication fidelity
- System integration

Laboratory synthesis of alternative nucleobases demonstrates that many other configurations prove chemically viable but functionally inferior. This suggests the natural nucleobases represent an optimized solution rather than a chemically inevitable outcome.

The evidence indicates that life's nucleobases embody a level of optimization unlikely to arise through undirected chemical processes. Their precise bond strengths, tautomeric preferences, and multiple interdependent optimizations point to purposeful design rather than chance or necessity. The mathematical improbability, combined with the absence of viable prebiotic selection mechanisms, presents a significant challenge to purely naturalistic explanations for their origin.

This nucleobase paradox - the selection of optimal configurations from vast chemical space while requiring simultaneous optimization of multiple parameters - remains unresolved within materialistic frameworks. The evidence aligns more closely with intelligent design, where foresight could guide the selection and optimization of these fundamental information-bearing molecules.

1. Introduction
DNA and RNA nucleobases represent a subset of chemical configurations so precise and optimized that their random emergence challenges conventional explanations. Research has identified over one million possible nucleobase variants, yet biological systems exclusively employ four specific bases in DNA and a slightly modified set in RNA. This analysis examines the evidence for optimization in these molecular choices and evaluates various explanations for their origin.

2. The Chemical Space of Nucleobase Possibilities

2.1 Theoretical Framework
The potential chemical space for nucleobase structures encompasses:
- Ring structure variations (single/double rings)
- Atomic composition alternatives
- Substituent group combinations
- Multiple tautomeric forms
- Various bonding patterns
- Isomeric arrangements

2.2 Quantitative Analysis of Chemical Space
Mathematical modeling reveals the scope of possibilities:
Base ring structures: ~10^4 variations
Substituent combinations: ~10^6 options
Tautomeric forms per structure: 2-10
Isomeric arrangements per base: ~10^2
Total theoretical combinations: >10^12

2.3 Structural Variations
Research has identified numerous viable alternatives:
- Modified ring systems
- Alternative hydrogen bonding patterns
- Different spatial arrangements
- Novel backbone connections
- Varied sugar attachments

3. Biological Specificity

3.1 Structural Requirements
Natural nucleobases exhibit precise specifications:
- Exact atomic composition
- Specific ring structures
- Defined tautomeric forms
- Precise hydrogen bonding capabilities
- Optimal spatial arrangements

3.2 Chemical Parameters
Key features include:
- C-O double bond energy: 30 kcal/mol higher than C-C/C-N bonds
- Specific hydrogen bond strengths
- Five-membered sugar rings
- 2.0 nm strand spacing
- Precise backbone angles

3.3 Functional Requirements
Biological nucleobases must satisfy multiple criteria:
- Information encoding capability
- Replication fidelity
- Chemical stability
- Metabolic accessibility
- System compatibility

4. Evidence for Optimization

4.1 Structural Optimization
Analysis reveals biological nucleobases optimize several parameters:

Information Storage: The precise molecular geometry enables efficient encoding of genetic data through complementary base pairing and stacking interactions.
Replication Accuracy: Base structures minimize tautomeric shifts and mispairing events, allowing high-fidelity DNA replication with error rates below 10^-9 per base pair.
Chemical Durability: Nucleobase structures resist degradation under physiological conditions, maintaining genomic integrity over multiple cell cycles.
Synthetic Economy: Nucleobase synthesis pathways utilize minimal metabolic resources while achieving maximal functional output.
Cellular Integration: Base structures interface precisely with cellular machinery, enabling recognition by polymerases and repair enzymes.

4.2 Thermodynamic Considerations
Thermodynamic analyses demonstrate distinct advantages of canonical nucleobases:

Aqueous Stability: Hydrolysis rates remain minimal compared to structural analogs, with half-lives exceeding years under physiological conditions.
Temperature Tolerance: Hydrogen bonding networks maintain integrity across thermal ranges from 0-100°C, accommodating diverse environmental conditions.
Tautomeric Balance: Keto-enol equilibrium strongly favors functional forms, with alternative tautomers appearing at frequencies below 10^-4.

4.3 System Integration Challenges
Nucleobase optimization extends beyond isolated properties to system-wide compatibility:

Backbone Interactions: Precise spatial arrangement enables 2.0 nm helix spacing, optimizing both stability and replication dynamics.
Recognition Elements: Surface features allow specific protein-DNA contacts, facilitating regulatory interactions and repair processes.
Energy Landscapes: Base stacking and pairing energies balance structural stability with strand separation requirements.

5. Mathematical Analysis

5.1 Probability Calculations
The probability of random selection of optimal configurations:
P(single base) = (specific structure/total possibilities) × (correct tautomer) × (proper spatial arrangement)
= (1/10^6) × (1/10) × (1/10^2)
= 10^-9

For all four bases:
P(total) = (10^-9)^4 = 10^-36

5.2 Time Requirements
Assuming maximum reaction rates:
Reactions per second: 10^12
Required trials: 10^36
Minimum time required: 10^24 seconds (>10^16 years)

5.3 Combinatorial Challenges
Multiple simultaneous optimizations required:
- Base pairing compatibility
- Backbone integration
- Enzymatic recognition
- Chemical stability
- Information capacity

6. Naturalistic Explanations and Their Limitations

6.1 Physical Necessity
Argument: Physical laws constrain possible structures
Limitations:
- Multiple viable alternatives exist
- No physical law requires these specific forms
- Synthetic analogs demonstrate functionality

6.2 Chemical Evolution
Argument: Natural selection operated on chemical systems
Limitations:
- No replication mechanism present
- No preservation of beneficial variants
- Insufficient time for exploration
- Multiple simultaneous optimizations needed

6.3 Self-Organization
Argument: Emergent properties guided development
Limitations:
- No mechanism for optimization
- No explanation for information content
- No account for system integration

7. Design Implications

7.1 Evidence for Design
Multiple factors indicate purposeful design:
- Optimal configuration selection
- Multiple parameter optimization
- System-wide integration
- Future function accommodation
- Information capacity

7.2 Design Parameters
Specific choices reflect design considerations:
- Bond strength optimization
- Spatial precision
- Tautomeric selection
- Integration capability
- Functional requirements

7.3 Design Logic
The arrangement of features demonstrates:
- Purposeful selection
- Forward planning
- System compatibility
- Efficiency optimization
- Error minimization

8. Alternative Theories

8.1 Multiple Universe Models
Proposed explanation: Our universe represents one of many possibilities
Limitations:
- No evidence for multiple universes
- No mechanism for selecting optimal chemistry
- Does not explain specific optimizations

8.2 Complexity Theory
Proposed explanation: Self-organizing principles guided development
Limitations:
- No demonstrated mechanism
- Cannot explain optimization
- Fails to account for information content

9. Future Research Directions

9.1 Synthetic Biology
Research priorities:
- Alternative nucleobase systems
- Functional testing of analogs
- Optimization parameter studies
- Design space exploration

9.2 Origins Research
Key areas:
- Chemical space mapping
- Selection mechanism investigation
- Alternative information systems
- Optimization pathway analysis

9.3 Theoretical Studies
Research needs:
- Computational modeling of alternatives
- Mathematical analysis of optimization
- System integration studies
- Information theory applications

10. Implications

10.1 Scientific Implications
The findings affect multiple fields:
- Origin of life research
- Synthetic biology
- Information theory
- Systems biology

10.2 Philosophical Implications
The research raises questions about:
- Naturalistic explanations
- Design detection
- Information origin
- Biological complexity

10.3 Practical Applications
Understanding has implications for:
- Synthetic genetic systems
- Drug design
- Biotechnology
- Information storage

11. Conclusions
The evidence demonstrates that biological nucleobases represent an optimized solution to multiple chemical and biological challenges. The probability calculations, optimization evidence, and system integration requirements strongly suggest purposeful design rather than random processes. The nucleobase paradox - selecting optimal configurations from an enormous possibility space while requiring simultaneous optimization of multiple parameters - remains a fundamental challenge to theories of chemical evolution.

Future research may reveal additional layers of optimization and design in these fundamental biological molecules. The implications extend beyond origin of life studies to synthetic biology, drug design, and information storage technology. Understanding the principles underlying nucleobase optimization provides valuable insights for both theoretical research and practical applications.

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