Biochemical fine-tuning - essential for life

Biochemical fine-tuning - essential for life

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

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

AmazingWatson–Crick base-pairing
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

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 for 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.
















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

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

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 ?

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

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

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

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

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.

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.