Biochemical fine-tuning - essential for life

Biochemical fine-tuning - essential for life

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

Fine-tuned regulation of nucleotide metabolism to ensure DNA replication with high fidelity is essential for proper development in all free-living organisms 3

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

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 (see Figure 16.2).



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 (see Figure 16.3).



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. 

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1. Barrow, FITNESS OF THE COSMOS FOR LIFE,  Biochemistry and Fine-Tuning, page 352
2. Barrow, FITNESS OF THE COSMOS FOR LIFE,  Biochemistry and Fine-Tuning, page 154

3. https://www.nature.com/articles/s41598-018-22145-8

Perfect Timing 1
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 life- time 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, 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 dam- aged 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 enzyme 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.

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.

1. Cell's design, F.Rana, page 119

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

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.hk/10.1104/pp.17.00863

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.

Using statistical methods to model the fine-tuning of molecular machines and systems

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. 

1.https://sci-hub.st/https://www.sciencedirect.com/science/article/pii/S0022519320302071?fbclid=IwAR1EVfJN5Cznwo1XM6uUSetSsW4qS0_k2uqxSR43bkDQ_W3DU-8tySWlcUA