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

Otangelo Grasso: This is my library, where I collect information and present arguments developed by myself that lead, in my view, to the Christian faith, creationism, and Intelligent Design as the best explanation for the origin of the physical world.

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Proteins and Protein synthesis


There are billions of known protein sequences.

The publication in 1958 of the first 3D structure of protein at an atomic resolution [Kendrew J.C et al., 1958] triggered a series of research projects aiming to uncover the principles behind protein folding.

Proteins are structures made by the direction of complex semantophoretic macromolecules that carry genetic information: DNA. The word protein comes from the Greek “proteos” which means “of prime importance,” “primary” or “first place.”

Proteins are the working horses of cells, performing all kinds of different tasks and functions. Proteins are responsible for the growth and maintenance of tissues, manufacturing, and processing of chemical compounds, they make biological structures, act as messengers, promote intracellular homeostasis, transcribe, translate, act as molecular taxis, transport molecules, form molecular highways, they anchor filaments, they participate in the formation of cellular structures, produce energy, etc. Proteins activate, bind, break, coordinate, confer positional information, direct, transmit force, generate, guide, help to organize, inform, convey positional information and rules, mediate, modulate, organize, orient,  provoke changes, regulate, signal, stretch, specify, and perform many other variated functions.

The chemical properties of the amino acids of proteins determine the biological activity of the protein. Proteins not only catalyze all (or most) of the reactions in living cells, they control virtually all cellular process. In addition, proteins contain within their amino acid sequences the necessary information to determine how that protein will fold into a three dimensional structure, and the stability of the resulting structure. The field of protein folding and stability has been a critically important area of research for years, and remains today one of the great unsolved mysteries. It is, however, being actively investigated, and progress is being made every day.

Marcel Filoche (2019): Enzymes speed up biochemical reactions at the core of life by as much as 15 orders of magnitude. Yet, despite considerable advances, the fine dynamical determinants at the microscopic level of their catalytic proficiency are still elusive. Rate-promoting vibrations in the picosecond range, specifically encoded in the 3D protein structure, are localized vibrations optimally coupled to the chemical reaction coordinates at the active site. Remarkably, our theory also exposes a hitherto unknown deep connection between the unique localization fingerprint and a distinct partition of the 3D fold into independent, foldspanning subdomains that govern long-range communication. The universality of these features is demonstrated on a pool of more than 900 enzyme structures, comprising a total of more than 10,000 experimentally annotated catalytic sites. Our theory provides a unified microscopic rationale for the subtle structure-dynamics-function link in proteins. The intricate networks of metabolic cascades that power living organisms ultimately rest on the exquisite ability of enzymes to increase the rate of chemical reactions by many orders of magnitude.

Researchers are debating whether function or structure first appeared in primitive peptides September 23, 2013
Proteins Red protein structure, generictraverse the width and breadth of cells to carry signals and cargo from one end to another, package and replicate DNA, build scaffolds to give cells their shapes, break down and take up nutrients, and so much more. But how often do we stop to ask: How did these diverse and sophisticated molecular machines come to be? Despite proteins' profound impact on life, their origin is not well understood. What caused a string of amino acids to start doing something? Or are strings of amino acids inherently programmed to do things? These are questions with which researchers in the protein-origin field have been grappling.

Researchers have a better grasp of the processes of selection and evolution once a function appears in a peptide. “Once you have identified an enzyme that has some weak, promiscuous activity for your target reaction, it’s fairly clear that, if you have mutations at random, you can select and improve this activity by several orders of magnitude,” says Dan Tawfik at the Weizmann Institute in Israel. “What we lack is a hypothesis for the earlier stages, where you don’t have this spectrum of enzymatic activities, active sites and folds from which selection can identify starting points. Evolution has this catch-22: Nothing evolves unless it already exists.

François Jacob: Evolution and Tinkering Jun. 10, 1977
A sequence of a thousand nucleotides codes for a medium-sized protein. The probability that a functional protein would appear de novo by random association of amino acids is practically zero. In organisms as complex and integrated as those that were already living a long time ago, creation of entirely new nucleotide sequences could not be of any importance in the production of new information.

A. G. CAIRNS-SMITH Seven clues to the origin of life, page 30:
Nothing evolves that is not somehow tied into the successions of messages. Nor could the precision of manufacture have been much less if it was enzymes that were needed right away. Darwin persuades us that the seemingly purposeful construction of living things can very often, and perhaps always, be attributed to the operation of natural selection. A clumsy enzyme is a good bit worse than useless if it is continually transforming molecules the wrong way, or transforming the wrong molecules. More and more molecules would be produced that had been wrongly put together, and these would include components for RNA adaptors, ribosomes, etc. - leading to further badly made enzymes and a rapid slide into chaos. Nor does it take much for an enzyme to become incompetent. The whole technique of operation requires that the protein message folds up in a way that depends on the sequence of amino acid units. Even having only one mistake, one wrongly inserted amino acid, can wreck any chance of a correct folding; and more than a few mistakes are almost bound to. It is not just the sheer size of even the smallest libraries; it is not just that nucleotide units are rather complex in themselves, and rather difficult to join together (because Nature is on the side of keeping them apart); it is not just the need for enzymes, here, there and everywhere; it is not just that enzymes are of little use unless they have been made properly; it is not just that ribosomes are so very sophisticated - and look as though they would have to be to do their job; it is not just such questions relating to the particular kind of life that we are familiar with. There seems also to be a more fundamental difficulty. Any conceivable kind of organism would have to contain messages of some sort and
equipment for reading and reprinting the messages: any conceivable organism would thus seem to have to be packed with machinery and as such need a miracle (or something) for the first of its kind to have appeared. That's the problem.

How Did Protein Synthesis Evolve?
The molecular processes underlying protein synthesis in present-day cells seem inextricably complex. Although we understand most of them, they do not make conceptual sense in the way that DNA transcription, DNA repair, and DNA replication do. It is especially difficult to imagine how protein synthesis evolved because it is now performed by a complex interlocking system of protein and RNA molecules; obviously the proteins could not have existed until an early version of the translation apparatus was already in place. As attractive as the RNA world idea is for envisioning early life, it does not explain how the modern-day system of protein synthesis arose.
Molecular biology of the cell, 6th ed. pg. 365

The corresponding DNA sequences dictate the amino acid sequences.  Specific functionality of a given protein is defined by a unique spatial positioning of its amino acid side chains and prosthetic groups, suggesting that such a specific spatial arrangement of functional groups in biologically active proteins is defined by their unique 3D structures predetermined by the unique amino acid sequences encoded in unique genes.

Estimating the prevalence of protein sequences adopting functional enzyme folds.
Combined with the estimated prevalence of plausible hydropathic patterns (for any fold) and of relevant folds for particular functions, this implies the overall prevalence of sequences performing a specific function by any domain-sized fold may be as low as 1 in 10(77), adding to the body of evidence that functional folds require highly extraordinary sequences.

Proteins: how they provide striking evidence of design


Proteins are evidence of intelligent design par excellence. Instructional/specified complex information is required to get the right amino acid sequence which is essential to get functionality in a vast sequence space ( amongst trillions os possible sequences, rare are the ones that provide function ), and every protein is irreducibly complex in the sense, that a minimal number of amino acids are required for each protein to get function. This constitutes an insurmountable hurdle for the origin of life scenarios based on naturalistic hypotheses since unguided random events are too unspecific to get functional sequences in a viable timespan. Another true smack-down is the fact that single proteins or enzymes by themselves confer no advantage of survival at all, and have by their own no function. There is no reason why random RNA strands would become self-replicating. And even IF that were the case, so what? There would be no utility for them unless at least 50 different precisely arranged and correctly interlinked enzymes and proteins, each with its specific function, would interlink in a complex, just right metabolic network, and be encapsulated in a complex membrane with gates and pores, and in a precisely finely tuned and balanced homeostatic ambiance. Energy production and supply to each protein would also have to be fully set up right from the start...... hard to swallow. But if your wish of naturalism to be true is strong enough, just shut your reason up, and believe this. Blindly.

It is not surprising that various studies on evolving proteins have failed to show a viable mechanism. One study concluded that 10^63 attempts would be required to evolve a relatively short protein. And another study concluded that 10^70 attempts would be required. So something like 10^70 attempts are required yet proponents of evolution estimate that only up to a probability of 10^43 attempts would be in the realm of possible. In other words, there is a shortfall of 27 orders of magnitude. But it gets worse.  

The impossible task to synthesize proteins on a prebiotic earth without external direction


Eliminative inductions argue for the truth of a proposition by arguing that competitors to that proposition are false. There was no sufficient nitrogen fixation on a prebiotic earth. The sufficiency of ammonia has also been brought into question. The source of sorting out of right-handed DNA and left-handed amino acids on a prebiotic earth is unsolved for decades. A recent science paper reported that the set of amino acids selected, being used in life, appears to be near ideal. Why the particular 20 amino acids were selected to be encoded by the Genetic Code remains a puzzle. This is nothing short than astounding. Why were they selected amongst over 500 different ones known? Amino acid synthesis requires essential regulation. How could that have been achieved without evolution? Regulation requires a regulator - or - intelligence.

Lifeless matter has no teleological goal to regulate things. How the amino acids would and could have been bonded together in the correct manner without the Ribosome is another unsolved question. The probability is far higher that polymers would disintegrate, rather than the opposite. How could natural processes have foresight, which seems to be absolutely required, to "know" which amino acid sequences would provoke which forces, and how they would fold the protein structure to get functional for specific purposes within the cell? Let's consider, that in order to have a minimal functional living cell, at least 561 proteins and protein complexes would have to be fully setup, working, and interacting together to confer a functional whole with all life-essential functions.

Many proteins require " help " proteins to fold correctly. Also, some which were essential for life to begin. How should and could natural nonintelligent mechanisms forsee the necessity of chaperones in order to get a specific goal and result, that is functional proteins to make living organisms? Nonliving matter has no natural " drive " or purpose or goal to become living. The make of proteins to create life, however, is a multistep process of many parallel acting complex metabolic pathways and production-line like processes to make proteins and other life essential products like lipids, carbohydrates etc. The right folding of proteins is just one of several other essential processes in order to get a functional protein. But a functional protein by its own has no function unless correctly embedded through the right order of assembly at the right place.

Last not least, this is probably one of the most screaming problems: For biological cells to make proteins, and direct and insert them to the right place where they are needed, at least 25 unimaginably complex biosyntheses and production-line like manufacturing steps are required. Each step requires extremely complex molecular machines composed of numerous subunits and co-factors, which require the very own processing procedure, which makes its origin an irreducible  catch22 problem.

Medical Research Council Unit for the Study of Molecular Biology, Cavendish Laboratory, Cambridge

The nature of protein synthesis:
The basic dilemma of protein synthesis has been realized by many people, but it has been particularly aptly expressed by Dr A. L. Dounce (1956); My interest in templates, and the conviction of their necessity, originated from a question asked me on my PhD oral examination by Professor J. B. Sumner. He enquired how I thought proteins might be synthesized. I gave what seemed the obvious answer, namely, that enzymes must be responsible. Professor Sumner then asked me the chemical nature of enzymes, and when I answered .that enzymes were proteins or contained proteins as essential components, he asked whether these enzyme proteins were synthesized by other enzymes and so on ad Infinitum. The dilemma remained in my mind, causing me to look for possible solutions that would be acceptable, at least from the standpoint of logic. The dilemma, of course, involves the specificity of the protein molecule, which doubtless depends to a considerable degree on the sequence of amino acids in the peptide chains of the protein. The problem is to find a reasonably simple mechanism that could account for specific sequences without demanding the presence of an ever-increasing number of new specific enzymes for the synthesis of each new protein molecule. It is thus clear that the synthesis of proteins must be radically different from the synthesis of polysaccharides, lipids, co-enzymes and other small molecules; that it must be relatively simple, and to a considerable extent uniform throughout Nature; that it must be highly specific, making few mistakes; and that in all probability it must be controlled at not too many removes by the genetic material of the organism.

a kinases is an enzyme that catalyzes the transfer of phosphate groups from high-energy, phosphate-donating molecules to specific substrates.
Isomerases are a general class of enzymes that convert a molecule from one isomer to another.
dehydrogenase (also called DH or DHase in the literature) is an enzyme belonging to the group of oxidoreductases that oxidizes a substrate by reducing an electron acceptor, usually NAD+/NADP+ or a flavin coenzyme such as FAD or FMN.

Lieven DEMEESTER Organic Production Systems: What the Biological Cell Can Teach Us About Manufacturing 3-2004
Biological cells run complicated and sophisticated production systems. The study of the cell’s production technology provides us with insights that are potentially useful in industrial manufacturing. When comparing cell metabolism with manufacturing techniques in the industry, we find some striking commonalities assures quality at the source, and uses component commonality to simplify production.  The organic production system can be viewed as a possible scenario for the future of manufacturing. We try to do so in this paper by studying a high-performance manufacturing system - namely, the biological cell. A careful examination of the production principles used by the biological cell reveals that cells are extremely good at making products with high robustness, flexibility, and efficiency. Section 1 describes the basic metaphor of this article, the biological cell as a production system, and shows that the cell is subject to similar performance pressures. Section 4 further deepens the metaphor by pointing out the similarities between the biological cell and a modern manufacturing system. We then point to the limits of the metaphor in §5 before we identify, in §6, four important production principles that are sources of efficiency and responsiveness for the biological cell, but that we currently do not widely observe in industrial production. For example, the intestinal bacterium, Escherichia coli,  runs 1,000–1,500 biochemical reactions in parallel. Just as in manufacturing, cell metabolism can be represented by flow diagrams in which raw materials are transformed into final products in a series of operations. 

With its thousands of biochemical reactions and high number of flow connections, the complexity of the cell’s production flow matches even the most complex industrial production networks we can observe today.  The performance pressures operating on the cell’s production system also exhibit clear parallels with manufacturing. Both production systems need to be fast, efficient, and responsive to environmental changeSpeed and range of response, as well as efficiency of its production systems, are clearly critical to the biological cell. Biologists have made the argument that the evolution of the basic structure of modern cells has largely been driven by “alimentary efficiency,” or the input-output efficiency of turning available nutrients into energy and basic building blocks. In addition, it is clear that in dynamic environments, the ability of the cell to react quickly and decisively is vital to ensure survival and reproduction.  Given the “manufacturing” nature of cell biochemistry and the comparable performance pressures on it, one should not be surprised to find interesting solutions developed by the cell that are applicable in manufacturing—especially since “cell technology” is much older and more mature than any human technology. The cell never forecasts demand; it achieves responsiveness through speed, not through inventories.

The limits to responsiveness depend only on the capacity limits of the enzymes in a particular pathway. The corresponding mechanism in manufacturing is referred to as a pull system. It produces only in response to actual demand, not in anticipation of forecast demand, thus preventing overproduction. While it is difficult to make direct comparisons with manufacturing plants, some case examples illustrate that the cell operates with little waste, even in regulating its pathways. In a U.S. electric-connectors factory in the early 1990s, 28.6% of plant labor was devoted to control and materials handling, while the figure was 14.9% in a simpler and leaner Japanese plant. In a house-care products plant, a cost analysis revealed that at least 14% of production costs were incurred by production planning and quality assurance. With its 11% of regulatory genes, the cell seems to set a pretty tight benchmark for regulation efficiency. The cell also uses quality-management techniques used in manufacturing today. The cell invests in defect prevention at various stages of its replication process, using 100% inspection processes, quality assurance procedures, and foolproofing techniques. An example of the cell inspecting each and every part of a product is DNA proofreading. As the DNA gets replicated, the enzyme DNA polymerase adds new nucleotides to the growing DNA strand, limiting the number of errors by removing incorrectly incorporated nucleotides with a proofreading function. An example of quality assurance can be found in the use of helper proteins, also called “chaperones.” These make sure that newly produced proteins fold themselves correctly, which is critical to their proper functioning. Finally, as an example of foolproofing, the cell applies the key-lock principle to guarantee a proper fit between substrate and enzyme, i.e., product and machine. The substrate fits into a pocket of the enzyme like a key into a lock, ensuring that only one particular substrate can be processed.

This is comparable with poka-yoke systems in manufacturing. An everyday example of poka-yoke is the narrow opening for an unleaded gasoline tank in a car. It prevents you from inserting the larger leaded fuel nozzle. The cell’s pathways are designed in such a way that different end products often share a set of initial common steps (as is shown in Figure 2). For example, in the biosynthesis of aromatic amino acids, a number of common precursors are synthesized before the pathway splits into different final products.   Interestingly, the intermediates used for “products” and “machines” (enzymes) are identical. In other words, the cell can easily degrade an enzyme into its component amino acids and use these amino acids to synthesize a new enzyme (a “machine”), replenish the central metabolism, or make another molecule (a “product”), e.g., a biogenic amine. It seems an amazing achievement by the cell to build the complexity and variety of life with such a small number of components. Imagine that all industrial machines were made of only 20 different modules, corresponding to the 20 amino acids from which all proteins are made. As we further explain below, this modular approach allows the cell to be remarkably efficient and responsive at the same time.

Basically, with both products and machines being built from just a few recyclable components, the cell can efficiently produce an enormous variety of products in the appropriate quantities when they are needed.  At any moment, synthesis and breakdown for each enzyme happen in the cell. The constant renewal eliminates the need for other types of “machine maintenance.” Assembly and disassembly of the cell’s machines are so fast and frictionless that they allow a scheme of constant machine renewal.  The cell has pushed this principle even further. First, it does not even wait until the machine fails, but replaces it long before it has a chance to break down. And second, it completely recycles the machine that is taken out of production. The components derived from this recycling process can be used not only to create other machines of the same type, but also to create different machines if that is what is needed in the “plant.” This way of handling its machines has some clear advantages for the cell. New capacity can be installed quickly to meet current demand. At the same time, there are never idle machines around taking up space or hogging important building blocks. Maintenance is a positive “side effect” of the continuous machine renewal process, thereby guaranteeing the quality of output. Finally, the ability to quickly build new production lines from scratch has allowed the cell to take advantage of a big library of contingency plans in its DNA that allow it to quickly react to a wide range of circumstances.

KUMAR SELVARAJOO: Production Equipment Is Added, Removed, or Renewed Instantly 22 October 2008
The capacity of the cell’s pathways can be adjusted almost immediately if the demand for its products changes. If the current capacity of a pathway is insufficient to meet demand, additional enzymes are “expressed” to generate more capacity within a certain range. Once the demand goes down, these enzymes are broken down again into their basic amino acids. This avoids waste as the released amino acids are then used for the synthesis of new proteins. At any moment, synthesis and breakdown for each enzyme happen in the cell. The constant renewal eliminates the need for other types of “machine maintenance.” Assembly and disassembly of the cell’s machines are so fast and frictionless that they allow a scheme of constant machine renewal. In some industrial manufacturing settings, we are also witnessing signs of the emergence of flexible capacity. Some of these companies do not repair their manufacturing equipment, but have it replaced. Take, for example, a contract manufacturer in Singapore that provides semiconductor assembly and test services for INTEL, AMD, and others. Its manufacturing equipment includes die bonders, wire bonders, and encapsulation and test equipment, all organized in pools. As soon as one machine goes down, the managers work with the equipment supplier to make a one-to-one replacement. All this goes very rapidly indeed. This policy makes sense because the low cost of a machine compared to the cost of downtime makes it economically feasible to have a couple of machines idle in the somewhat longer repair cycle. One can imagine this practice spreading as manufacturing equipment becomes more standardized and less expensive, and as the cost of a capacity shortage increases. In this scenario, machines are still repaired, although at the supplier site rather than on the manufacturing floor. The cell has pushed this principle even further. First, it does not even wait until the machine fails, but replaces it long before it has a chance to break down. And second, it completely recycles the machine that is taken out of production. The components derived from this recycling process can be used not only to create other machines of the same type, but also to create different machines if that is what is needed in the “plant.” This way of handling its machines has some clear advantages for the cell. New capacity can be installed quickly to meet current demand. At the same time, there are never idle machines around taking up space or hogging important building blocks. Maintenance is a positive “side effect” of the continuous machine renewal process, thereby guaranteeing the quality of output. Finally, the ability to quickly build new production lines from scratch has allowed the cell to take advantage of a big library of contingency plans in its DNA that allow it to quickly react to a wide range of circumstances.

Complex living systems have shown remarkably well-orchestrated, self-organized, robust, and stable behavior under a wide range of perturbations. Simple linear rules govern the response behavior of biological networks in an ensemble of cells. It is daunting to know why such simplicity could hold in a complex heterogeneous environment. Provided physical reasons can be explained for these phenomena, major advancement in the understanding of basic cellular processes could be achieved. Cellular systems are characterized by the complex interplay of DNA, RNA, proteins, and metabolites to achieve specific goals: cell division, differentiation, apoptosis, etc.

My comment: Specific goals. That is pure teleology. And these specific goals had to emerge, if naturalism is true, by random, unguided accidents.

Although this is valuable advancement in modern biology, cellular properties such as growth, ageing, morphology, and immune response still remain largely elusive.

My comment: If morphology remains elusive, evolution remains elusive too. Evolution influences directly morphology, Cell shape, body shape and form, and if the mechanisms that determine these things are not understood in the first place, how they can change, cannot be known either.

To understand such complex and dynamic behavior of living systems, which may be governed by key regulatory principles, the development of systems biology approaches which integrates theoretical concepts with experimental methodologies is required. Typically, random deletions, mutations, or duplications of genes have been shown not to affect the overall network behavior or phenotypic outcome of living systems, revealing the persistence of stable and robust behavior under diverse perturbations. Biological networks are not connected randomly, but centers around a small proportion of “hub” and “connector” elements. Catastrophic failure can occur due to the lost of function of such crucial family of “hub/connector” molecules. Well-defined signal transduction module in living systems cannot result through random collisions or interactions.

Several studies have indicated that ensemble of cells display collective behavior which is deterministic (averaging), robust, highly predictable, and stable under drastic environment perturbations. Under these circumstances, we have reviewed that simple linear rules derived from the first-order mass-action response equations can be used to determine the causal relationships between biological networks. This simplicity surprisingly holds in a highly anticipated complex heterogeneous environment.

Franklin M. Harold: in The Way of the Cell (Oxford: Oxford University Press, c. 2001, 205.)
Evolution of the fact of Intelligent Design
The truth of Intelligent Design is passing through three stages. First, it was ridiculed ( past ) Second, it is violently opposed ( present ). Third, it is accepted as being self-evident. ( future )

“At the cellular level, we find an incredibly intricate and “Who-ish” world where each single-celled organism is a high-tech factory complete (as one scientist described it) with artificial languages and their decoding systems, memory banks for in formation storage and retrieval, elegant control systems regulating the automated assembly of parts and components, error fail-safe and proofreading devices utilized for quality control, assembly processes involving the principles of prefabrication and modular construction…”

We may think of a cell as an intricate and sophisticated chemical factory. Matter, energy and information enter the cell from the environment, while waste products and heat are discharged. The object of the entire exercise is to replicate the chemical composition and organization of the original cell, making two cells grow where there was one before. Even in the simplest cells, this calls for the collaborative interactions of many thousands of molecules large and small, and requires hundreds of concurrent chemical reactions.These break down foodstuff, extract energy, manufacture precursors, assemble constituents, note and execute genetic instructions and keep all this frantic activity coordinated. The term “metabolism” designates the sum total of all these chemical processes, derived from the Greek word for “change.” Biochemistry, then, is the study of the chemical basis of all biological activity.

Enzymes derive meaning from being parts of a larger whole, the metabolic web. How enzymes perform their catalytic feats, greater by many orders of magnitude than those of inorganic catalysts, has long been one of the central questions in biochemistry. The heart of the matter is the specific, intimate, and tight binding of the substrate (or substrates) to the enzyme. Proteins (and virtually all enzymes are proteins) are not shapeless blobs, but sculptured objects, equipped with crannies and cavities that admit particular molecules, while excluding others. Binding commonly entails changes in the configuration of both substrate and enzyme, inducing stresses and strains that contribute to the mechanism of catalysis. Besides, the catalytic site supplies chemically active groups in the form of amino acid side-chains that actually participate in the reaction. The catalytic site is tailored, as it were, to its particular task, linking its structure to its function.

The genome of E. coli encodes approximately 4,000 proteins, that of yeast 6,000; it takes 3.000,000 proteins or more to make a man. What do they all do? Many proteins are enzymes, but by no means all. Some proteins serve as the building blocks of structural scaffolding. Some make tracks for the movement of organelles, itself mediated by motor proteins. Proteins act as receptors for signals from within the cell or from the outer world; they transport nutrients, waste products and viruses across membranes. Proteins also commonly modulate the activities of other proteins, or of genes. The general principle is that, except for the storage and transmission of genetic information and the construction of compartments, almost all that cells do is done by proteins. The explanation for the functional versatility of proteins is not chemical so much as physical. Amino acid chains can fold into a variety of shapes, globular and fibrous, each determined by the sequence of the amino acids that make up the protein in question. As they fold, each generates a unique contour with its own pattern of structural features: rods and hinges, platforms and channels, holes and crevices. Moreover, proteins are flexible and dynamic constructs that commonly change shape when they interact with ligands or with each other. The range of stable configurations that amino acid chains can assume is wider than that of other classes of macromolecules, nucleic acids in particular; and their flexibility permits all sorts of mechanical actions demanded of molecular machines.

Proteins, as catalysts and structural elements, are part of biochemical tradition; more recently we have come to see many of them as mechanical devices that rely on energized motion to perform their tasks. Even enzymes can be profitably looked at from this point of view: with the growing catalogue of enzyme structures has come the recognition that active sites and their elements commonly undergo rearrangement as part of the catalytic cycle and its regulation. Other proteins are there to bring about overt movement, either of molecules or of larger objects. Transport carriers reorient the binding site from one membrane surface to the other, and back again; sometimes the mechanical cycle is coupled to an energy source, turning the carrier into a pump. Students of eukaryotic cells are finding ever more motor proteins that translocate vesicles, chromosomes, or elements of the cytoskeleton from one place to another. The most familiar example is myosin, whose cyclic change of conformations underlies muscle contraction and some instances of cell motility. And bear in mind ribosomes and the polymerases that transcribe and replicate genetic information: energized movements are central to their operations. As we unravel the molecular workings of life, the cell presents itself as an assemblage of tiny machines; mundane mechanical engineering looms as large as the subtle flow of energy and information.

The problem of the origin of the hardware and software in the cell is far greater than commonly appreciated

The estimated number of sequences capable of adopting the h repressor fold is still an exceedingly small fraction, about one in 10^63 of the total number of possible 92-residue sequences.

The interdependent and irreducible structures required to make proteins

Peptide bonding of amino acids to form proteins and its origins

Forces Stabilizing Proteins - essential for their correct folding

Proteins: how they provide striking evidence of design

Biosynthesis of Iron-sulfur clusters, basic building blocks for life  

Titin the largest proteins known and titin-telethonin complex - the strongest protein bond found so far in nature

On reading "Signature in the Cell"

Last edited by Otangelo on Sun Jun 04, 2023 8:33 am; edited 7 times in total




Protein homeostasis: By evolution, or design? 

Brant M. Webster: Protein homeostasis from the outside in  08 July 2020
Secretory proteins ( A secretory protein is any protein, whether it be endocrine or exocrine, which is secreted by a cell. Secretory proteins include many hormones, enzymes, toxins, and antimicrobial peptides) undergo multiple rounds of co- and post-translational quality control checks inside the cell. Maintaining the integrity of the proteome is essential for cell viability, yet proteins continuously face destabilizing pressures that threaten function . Proteins are therefore subject to constant surveillance by protein homeostasis networks that monitor quality throughout the protein life cycle—from synthesis to folding, trafficking, and degradation

My comment: That means, gaining new functions of proteins by evolutionary pressures is much harder. This error surveillance network has to be cheated. It is like someone hiring a constant team of surveyors that monitor the proper functioning of a complex machine.

Strikingly, a large portion of the proteome is physically separated from these protective measures, specifically secreted proteins and extracellular domains of integral plasma membrane proteins. Similarly to intracellular proteins, secretory proteins are closely monitored during synthesis and folding in the endoplasmic reticulum (ER) and undergo further quality checks at the Golgi and cytosolic side of the plasma membrane . The existence of these spatially segregated, yet overlapping quality control measures prompts the question “What happens if a protein misfolds after it is secreted?” In the same vein as “If a tree falls in a forest and no one is around to hear it, does it make a sound?,” if a protein misfolds outside the cell, does it know? Does the cell, tissue, or organism care? A spectrum of diseases featuring deposits of extracellular aggregates emphasises the dangers of misfolded extracellular proteins if left unchecked. 

A growing consensus of data propose a general strategy of extracellular protein homeostasis: holdases bind to and prevent the aggregation of misfolded proteins while directing them for endocytosis and lysosomal degradation. The emerging set of rules governing the integrity of the worm extracellular proteome seem to be in line with mammalian models. This work introduces a facet of extracellular protein homeostasis comprising a putative UPR-like signalling cascade to protect against the toxic effects of misfolded proteins outside the cell. We predict that the genetic amenability and short lifespan of the worm combined with tracking of endogenous aggregation-prone proteins in intact organisms holds immense potential, allowing for comprehensive understanding of the role of extracellular quality control in tissue and organismal physiology. 1

My comment: In order to have error-check and quality control, it has to be known beforehand what the correct, and the wrong state of affairs is. It has also to be known how to implement these monitoring systems, and once an error is detected, one has to know as well how to deal with the problem. This is all evidence AGAINST evolution, and evidence FOR design.

Judith Matavacas: Update on the Protein Homeostasis Network in Bacillus subtilis 08 March 2022
Protein homeostasis is fundamental to cell function and survival. It relies on an interconnected network of processes involving protein synthesis, folding, post-translational modification and degradation as well as regulators of these processes. Maintaining integrity of a more complex and unstable proteome has been dealt with by increasing cellular chaperone levels, as well as promoting cooperation between them. 2

My comment: Observe the words, and vocabulary, that the authors use. It is permeated with teleology. Intelligent agents with goals and foresight implement quality control checks and measures, surveillance of homeostasis networks, monitor quality,  apply general strategies,  implement a set of rules that govern things, signaling cascades for protecting things, implement an interconnected network of processes, regulate things and implement systems that promote cooperation. All these terms could be straight out from an engineering manual and handbook. Applying the origin of such actions to a non-designed, non-intelligent, mindless process is in short nonsensical, and absurd. How many absurd claims and evolutionary propositions must the faithful of evolution swallow, in order to wake up and have a flash of lucidness, to become aware that evolutionary biology proposint the idea from a last universal common ancestor to man is a big intellectual scam and lie ?

1. Brant M. Webster: Protein homeostasis from the outside in  08 July 2020
2. Judith Matavacas: Update on the Protein Homeostasis Network in Bacillus subtilis 08 March 2022




The odds against evolving new proteins

Biochemical Evolution-The Pursuit of Perfection
There are many examples of proteins where the sequence in one organism has an aspartate residue and that in another has glutamate. In fact many observed substitutions are far more radical than that, and we can find quite different amino acids substituting for one another in perfectly functional proteins. Contrary to what creationists may believe, there is a great deal of redundancy in protein structures, and it is far from the case that a protein sequence has to be exactly right. On the contrary, most protein functions can be fulfilled by a large number of known different sequences, not to mention all of the possible ways that are not yet known.




Review: J. W. Thornton (2022): Simple mechanisms for the evolution of protein complexity


Proteins are tiny models of biological complexity: specific interactions among their many amino acids cause proteins to fold into elaborate structures, assemble with other proteins into higher-order complexes, and change their functions and structures upon binding other molecules. 

Comment: Merriam-Webster describes the word "elaborate" as: "planned or carried out with great care, to produce by labor,
Synonyms: Adjective: complex, complicated, detailed, fancy, intricate, involved, sophisticated

Its hard to overlook the teleological aspect of the word. We can all agree that proteins are well-described as elaborate: Nucleopores for example have been described recently as "a massive complex of roughly 1,000 proteins that helps channel DNA instructions to the rest of the cell" 1 2

These complex features are classically thought to evolve ( so they are not certain) via long and gradual trajectories driven by persistent natural selection. But a growing body of evidence from biochemistry, protein engineering, and molecular evolution shows that naturally occurring proteins often exist at or near the genetic edge of multimerization  (MULTIPROTEIN COMPLEXES), allostery, and even new folds, so just one or a few mutations can trigger acquisition of these properties. These sudden transitions can occur because many of the physical properties that underlie these features are present in simpler proteins as fortuitous by-products of their architecture. Moreover, complex features of proteins can be encoded by huge arrays of sequences, so they are accessible from many different starting points via many possible paths. Because the bridges to these features are both short and numerous, random chance can join selection as a key factor in explaining the evolution of molecular complexity.

Comment: What Thornton et.al. conveniently do not mention, is that the origin of protein complexity does not start when life starts, but there has to be already a fully developed proteome to kickstart life. The question of how it all started from a random bunch of almost infinite different disordered molecules laying around prebiotically is a much harder task.

R. Mukhopadhyay (2013): Researchers have a better grasp of the processes of selection and evolution once a function appears in a peptide. “Once you have identified an enzyme that has some weak, promiscuous activity for your target reaction, it’s fairly clear that, if you have mutations at random, you can select and improve this activity by several orders of magnitude,” says Dan Tawfik at the Weizmann Institute in Israel. “What we lack is a hypothesis for the earlier stages, where you don’t have this spectrum of enzymatic activities, active sites and folds from which selection can identify starting points. Evolution has this catch-22: Nothing evolves unless it already exists.3

A minimal amount of instructional complex information is required for a gene to produce useful proteins. Minimal size of a protein is necessary for it to be functional. Thus, before a region of DNA contains the requisite information to make useful proteins, natural selection would not select for a positive trait and play no role in guiding its evolution. 

Understanding how living things acquired their complex features—structures and functions that arise from specific interactions among differentiated parts—has been a central aim of biology for centuries. 1

Comment: Thornton directs to the first paper with link no.1. Interesting, what in the introduction is being confessed: " The consensus among evolutionists seems to be (and has been for at least a century) that the morphological complexity of organisms increases in evolution, although almost no empirical evidence for such a trend exists. ( Thank you for pointing that out!) Most studies of complexity have been theoretical, and the few empirical studies have not, with the exception of certain recent ones, been especially rigorous; reviews are presented of both the theoretical and empirical literature. The paucity of evidence raises the question of what sustains the consensus, and a number of suggestions are offered, including the possibility that certain cultural and/or perceptual biases are at work. ( I could not agree more) 

Darwin supplanted divine agency with the evolutionary view: complexity arises through “numerous successive, slight modifications” under the influence of natural selection, because each step enhances functions that contribute to fitness. This scenario of gradual elaboration and optimization is well-supported in numerous cases.4-7

Comment:  Thornton now links to a few science papers, that supposedly back up the claim that " gradual elaboration and optimization is well-supported in numerous cases ". Shall we have a look if that is indeed factual ? 

K. E. Jones (2019): A fundamental concept in evolutionary biology is that life tends to become more complex through geologic time, but empirical examples of this phenomenon are controversial. 

Comment:  Something, between being well-supported, and being controversial, is quite a stretch if you ask me. 

One debate is whether increasing complexity is the result of random variations if there are evolutionary processes that actively drive its acquisition, and if these processes act uniformly across clades. 

Comment: We know that there is pre-programmed adaptation, but that does not say anything in regard to the transition from one phenotype to a completely different one with complex novelties, like limbs, eyes etc. ( which is what in the end is in dispute ) For more, see here: Non random mutations : How life changes itself: the Read-Write (RW) genome

The mammalian vertebral column provides an opportunity to test these hypotheses because it is composed of serially-repeating vertebrae for which complexity can be readily measured. Here we test seven competing hypotheses for the evolution of vertebral complexity by incorporating fossil data from the mammal stem lineage into evolutionary models. Based on these data, we reject Brownian motion (a random walk) and uniform increasing trends in favor of stepwise shifts for explaining increasing complexity. We hypothesize that increased aerobic capacity in non-mammalian cynodonts may have provided impetus for increasing vertebral complexity in mammals.

Comment: hypothesize and may have are not words used to describe confirmed and demonstrated facts, but characterizes speculation and guesswork!

At the very end of the paper, in the section "Discussion", the paper ends with: "Selection for higher activity levels combined with the release of respiratory constraints in cynodonts may have provided the trigger required to achieve vertebral complexity, and the subsequent biomechanical and ecological diversification of the presacral column in mammals"

Comment: If you were expecting more than speculation, you will be disappointed. If one wants to explain the origin of vertebra, the mechanisms involved in vertebra development have to be elucidated first,. Anatomical comparisons are entirely meaningless.

To understand novelty in evolution, we need to understand organisms down to their individual building blocks, down to the workings of their deepest components, for these are what undergo change.
Dr. Marc W. Kirschner: The Plausibility of Life: Resolving Darwin's Dilemma 2005

Osteogenesis is in fact an irreducibly complex process, and therefore, evolution is inadequate to explain its origin, as elucidated here: Origin and development of bones  ( Osteogenesis)
Furthermore, in order to explain the origin of such complex structures as a vertebra, which requires billions of cells, one has to explain each step, as i do here: 
How do biological multicellular complexity and a spatially organized body plan emerge?

The most famous is the modern vertebrate eye, which evolved from a simple light-sensitive precursor by sequentially adding cell types and more complicated relationships among tissues, each of which improved visual sensitivity or acuity.

Comment: Before addressing the evolution of vertebrate eyes, Thornton would do good to explain as well how eyespots (which are the starting point of Nilsson's paper) originated. I have yet to see a plausible account for that. Evolutionnews published my article on that, see here:  The Evolution of the Eye, Demystified  and then explain the origin of the visual cycle:  Origin of phototransduction, the visual cycle, photoreceptors and retina and the human eye: How the origin of the human eye is best explained through intelligent design

In the last half-century or so, a pageant of intricate forms has been revealed at a tiny new scale. Every protein is itself a complex system, because its physical and functional features depend on a large number of interactions among its many constituent amino acids. For example, a protein's ability to fold into its native tertiary structure depends on complementary steric, electrostatic, and hydrophobic interactions among scores or hundreds of residues.

Comment: Orchestrating these forces that permit the right folding that in the end will result in proteins with specific functions requires foresight and - intelligence: Forces Stabilizing Proteins - essential for their correct folding

The same is true of quaternary structure: most proteins assemble with other molecules into specific multimeric complexes, and the interfaces that hold these complexes together often involve dozens of tightly packed residues with a high degree of electrostatic and steric complementarity. Another form of complexity is allostery—changes in a protein's function caused by binding an effector molecule—which typically involves many amino acids to bind the effector and coupleing of binding to the active site. 

Comment: instantiating "Molecular Recognition Through Structural Complementarity" requires as well intelligence, as i point out here

During the last ~3.8 billion years, evolution has generated proteins with thousands of different folds, unique multimeric interactions, and varying modes of allosteric regulation.

Comment: Orchestration and timing of cellular processes require life-essential, precise timing, cross-regulation, coordination, the right sequence of processes, the right speed, at the right rate, there are checkpoint mechanisms, error checking, and repair at various stages. Question: What emerged first: protein synthesis, or the right, precise coordination of the whole process, and its respective proteins and signaling processes doing the job? For more, see here

This diversity presents a molecular version of the classic question about the evolution of biological complexity: how did the stepwise processes of evolution repeatedly produce complicated systems from simpler precursors? Darwin's model of gradual adaptive elaboration was developed to explain morphological and physiological complexity, but it has been assumed to apply as well to the evolution of complex molecular features. Intuitively, the view that protein complexity always evolves by long, consistently adaptive trajectories may seem sensible or even necessary, given certain assumptions. For a feature to evolve, the sequence states that encode it must arise by mutation and then be fixed in populations. 

Comment: Must be? Yes. If we presuppose philosophical naturalism and do not permit design in the explanatory framework as a possible alternative explanation.

Multimerization, allostery, and protein folds all involve elaborate arrays of interacting amino acids, so how else could they have been acquired if not by a long and specific series of many sequence changes? And, in turn, how could we explain the fixation of a long series of particular mutations if each step were not driven by the deterministic power of selection?

Comment: Does natural selection have deterministic power? Does it determine something? No, it does not. Natural selection is not an acting force but is passive. It does not invent something new.
R.Carter:‘Natural selection’ properly defined simply means ‘differential reproduction’, meaning some organisms leave more progeny than others based on the mutations they carry and the environment in which they live. 56

It has been suggested that such features might arise neutrally, but fixation by chance alone would be vanishingly improbable if many particular mutations are required. Recent advances in protein biochemistry and molecular evolution call into question the assumptions that underlie the argument for the gradual adaptive evolution of protein complexity. Of particular note are dramatic improvements in protein design, deep mutational scanning (which characterizes the functions of huge numbers of protein sequence variants), and ancestral protein reconstruction (which uses phylogenetics to infer the sequences of ancient proteins and experiments to determine the molecular functions and structures that existed in the deep past). This new body of work shows that just one or a few mutations can drive the acquisition of multimerization, allostery, and even new folds from natural precursors that lack these features; furthermore. It also explains why these short paths exist: simpler proteins often already possess most of the physical properties that underly these features. Moreover, the networks of sequences that yield multimerization, allostery, or a given protein fold appear to be immense, and they are closely intercalated at numerous places with the sequence networks of functional proteins that lack the feature. As a result, proteins can—and do—acquire new complex features by neutral processes. Contrary to the metaphor underlying the gradualist view, the complex features of proteins are not singular, massive mountain peaks that an evolving protein can climb only via a long trek under the deterministic engine of natural selection. Rather, many complex features are better conceived of as innumerable wrinkles, each small enough to be mounted in a single step (or just a few), which proteins repeatedly encounter as they wander through a vast multidimensional landscape of functional amino acid sequences.

Comment: Even if they do, so what? Does that explain biocomplexity and diversification, and the origin of organismal and organ and limb novelties?

(1) massive/infinite amounts of “natural” small changes;
(2) many beneficial/magical, random genetic mutations, producing novel, more complex structures over eons of time, from a “simple” virus or amoeba, to man; and
(3) Natural Selection – the continued survival (of fittest) of these different/new living Species (cf. speciation) & Families. ?

Macroevolution. Fact, or fantasy?

Another point: Imagine a production line in a factory. Many robots there are lined up, and raw materials are fed into the production line. The materials arrive at Robot one. It processes the first step. Then, when ready, the product moves on and is handed over to the next Robot. Next processing step. And that procedure repeats 17 times. In the end, there is a fully formed subpart, like the door of a car. That door is part of a larger object, like the finished car. That door by its own has no use unless mounted at the right place in the car.  Nobody would project a car door without visualizing the higher end up front, in the project and development stage, and based on the requirement, specify the complex shape of the door which precisely will fit the whole of the chassis of the car where it will be mounted. And the whole production line and each robot the right placement and sequence where each robot will be placed must be planned and implemented as well. Everything has to be projected with a higher-end goal in mind. And there is interdependence. If one of the robots ceases to work for some reason, the whole fabrication ceases, and the completion of the finished car cannot be accomplished. That means, a tiny mal connection of one of the robots in the production line of the door might stop the production of the door, and the finished car cannot be produced.

Metabolic pathways in cells are analogous to human-made production lines. They work in an integrated fashion together. If one enzyme or protein mutates to produce a different product, than that new product might not be useful for the next manufacturing step, and the whole thing breaks down.

Alone, and individually, each of the 17 enzymes that synthesize Chlorophyll can do nothing. But together, lined up like in a factory production line, they process the intermediate substrates, hand it over to the next, and the next, 17 manufacturing steps, one enzyme machine fine-tuned to produce the substrate, which the next enzyme can process, that in the end, makes the chlorophyll molecule, the most abundant organic compound found on earth, in bacteria, plants, algae, diatoms, plankton, corals and, oxygenating the oceans, make abundant marine life possible.

Chlorophyll by its own can do nothing. But together with many other Chlorophylls in the antenna complex, it can transfer, when energized to a higher energy state through photons, its resulting high-energy electron state to its adjacent Chlorophyll, and so down to the reaction center, and energize the P680 special Chlorophyll pair, and start the electron chain. But the lineup and order of these Chlorophylls cannot be just so. It must be just right. Each Chlorophyll must have the right distance, one from the other, to produce the energy transfer. And what an energy transfer that is - it's an engineering marvel !! It's almost 100% efficient, and done by quantum mechanical Förster resonance energy transfer principles !!! The stupendous ingeniosity cannot be enough outlined.... Human-made solar panels, in comparison, have just 20% efficiency...

The reaction center IMHO cannot operate and release an electron, if it does not find its replacement - which the oxygen-evolving complex provides.
If the oxygen-evolving complex would be not there, no oxygen would be released into the atmosphere and no respiration could occur, and no advanced life exist !!
Chlorophyll by its own in the antenna complex, will produce triplet states and burn the membrane where they are embedded. But Carotenoid chromophores do join them, and prevent triplet states to occur - they quench the solar energy when too strong, and release it as heath.

Yup, No Carotenoids, and you would probably not be here to read my lines. To make Carotenoids, it is another extremely complex biosynthesis process, but that's another story....

On the one side, you have an intelligent agency-based system of irreducible complexity of tight integrated, information-rich functional systems which have ready on-hand energy directed for such, that routinely generate the sort of phenomenon being observed.  And on the other side imagine a golfer, who has played a golf ball through a 12-hole course. Can you imagine that the ball could also play itself around the course in his absence? Of course, we could not discard, that natural forces, like wind, tornadoes, or rains or storms could produce the same result, given enough time.  the chances against it, however, are so immense, that the suggestion implies that the non-living world had an innate desire to get through the 12-hole course.

Irreducible Complexity: The existence of irreducible interdependent structures in biology is an undeniable fact

1. Shelly Fan: In Its Greatest Biology Feat Yet, AI Unlocks the Complex Proteins Guarding Our DNA June 14, 2022
2. Nuclear pore complexes. Design, or evolution ?
3. Rajendrani Mukhopadhyay: “Close to a miracle” Sept. 23, 2013
4. Katrina E. Jones: Stepwise shifts underlie evolutionary trends in morphological complexity of the mammalian vertebral column 07 November 2019




Metamorphic proteins: the Janus proteins of structural biology




Describing an enzyme or protein completely requires an understanding of its origins, evolution, architecture, function, and other important aspects. Here is a brief overview of some of the information that could be included in a comprehensive description:

Overall description

Its function

Function: This includes information on the biochemical reactions or processes that the protein/enzyme is involved in, as well as its substrate specificity, kinetic properties, and regulatory mechanisms. This may involve biochemical assays, enzymatic activity measurements, or other experimental techniques.

Its architecture

Architecture: This includes information on the three-dimensional structure of the protein/enzyme, including its folding pattern, active site, and any cofactors or ligands that may be associated with it. This may involve structural biology techniques such as X-ray crystallography, NMR spectroscopy, or cryo-electron microscopy.

describing the subunits
describing the action core
describing the co-factor
describing the biosynthesis of the co-factor

Its biosynthesis
Genetic information
is it made based on spliced genes in the spliceosome?
How is it synthesized
How are the subunits and co-factors synthesized
How are they assembled together

What forces hold the structure together

Describing its origin

Evolution: This includes information on how the protein/enzyme has evolved over time, including its phylogenetic relationships with other proteins/enzymes, and the mechanisms that have driven its evolution (e.g. natural selection, gene duplication and divergence, lateral gene transfer, etc.).

Phylogeny tree

Origins: This includes information on the molecular mechanisms that led to the emergence of the protein/enzyme in question. This may involve an analysis of the chemical and physical conditions that were present during the formation of life on Earth, as well as the various theories proposed to explain the origin of life.

Other factors:

Other factors that may be relevant to a complete description of a protein/enzyme include its cellular localization, how the cell knows where its localization is in the cell, 
post-translational modifications, 
interactions with other proteins or biomolecules

what has to be mentioned, to describe in an exhaustive, holistic manner, the biosynthesis pathway in the cell ?

To describe the biosynthesis pathway in a cell in an exhaustive and holistic manner, the following aspects should be mentioned:

The starting molecules or substrates involved in the biosynthesis pathway.

The enzymes and metabolic reactions involved in converting the substrates into the desired end products.

The regulation of the pathway, including the feedback mechanisms and regulatory molecules that control enzyme activity and gene expression.

The energy requirements for the pathway, including the sources of ATP and NADPH needed for biosynthesis.

The interconnections and crosstalk with other metabolic pathways in the cell, including anabolic and catabolic pathways.

The role of cofactors, vitamins, and minerals in supporting the biosynthesis pathway.

The final products of the pathway and their cellular functions, including their roles in metabolic and signaling pathways.

The metabolic fate of the end products, including the breakdown, excretion, or storage of the products in the cell.

By covering these aspects, one can provide a comprehensive description of the biosynthesis pathway in a cell.


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