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


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” 12

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

Of note:
Dollo’s law, the symmetry of time, and the edge of evolution - Michael Behe - 2009 Excerpt: We predict that future investigations, like ours, will support a molecular version of Dollo's law:,,, Dr. Behe comments on the finding of the study, "The old, organismal, time-asymmetric Dollo’s law supposedly blocked off just the past to Darwinian processes, for arbitrary reasons. A Dollo’s law in the molecular sense of Bridgham et al (2009), however, is time-symmetric. A time-symmetric law will substantially block both the past and the future. http://www.evolutionnews.org/2009/10/dollos_law_the_symmetry_of_tim.html From Thornton's Lab, More Strong Experimental Support for a Limit to Darwinian Evolution - Michael Behe - June 23, 2014 Excerpt: In prior comments on Thornton's work I proposed something I dubbed a "Time-Symmetric Dollo's Law" (TSDL).3, 8 Briefly that means, because natural selection hones a protein to its present job (not to some putative future or past function), it will be very difficult to change a protein's current function to another one by random mutation plus natural selection. But there was an unexamined factor that might have complicated Thornton's work and called the TSDL into question. What if there were a great many potential neutral mutations that could have led to the second protein? The modern protein that occurs in land vertebrates has very particular neutral changes that allowed it to acquire its present function, but perhaps that was an historical accident. Perhaps any of a large number of evolutionary alterations could have done the same job, and the particular changes that occurred historically weren't all that special. That's the question Thornton's group examined in their current paper. Using clever experimental techniques they tested thousands of possible alternative mutations. The bottom line is that none of them could take the place of the actual, historical, neutral mutations. The paper's conclusion is that, of the very large number of paths that random evolution could have taken, at best only extremely rare ones could lead to the functional modern protein. http://www.evolutionnews.org/2014/06/more_strong_exp087061.html "I (Behe) spent half of Chapter 8 (in "Darwin Devolves") on Thornton’s work, discussing why it shows deep and unexpected problems for Darwinian evolution." https://evolutionnews.org/2019/03/bullet-points-for-jerry-coyne/ Darwin Devolves: The New Science About DNA That Challenges Evolution - Behe - 2019 https://www.amazon.com/Darwin-Devolves-Science-Challenges-Evolution/dp/0062842617 When Darwin’s Foundations Are Crumbling, What Will the (Darwinian) Faithful Do? Excerpt: Here’s a summation of the evolutionary picture that has emerged, according to Behe (in his 2019 book "Darwin Devolves"): • The large majority of mutations are degradatory, meaning they’re mutations in which the gene is broken or blunted. Genetic information has been lost, not gained. • Sometimes the degradation helps an organism survive. • When the degradation confers a survival advantage, the mutation spreads throughout the population by natural selection. In genetics, a loss of information generally translates into a loss of function, so it might seem counterintuitive to suppose that a degradatory mutation would confer a survival advantage. Behe gives several examples, though, of instances where damaged genes have been shown to aid survival. In the case of the sickle-cell gene, for example, a single amino acid change causes hemoglobin to behave in a way that inhibits growth of the malaria microbe. It’s a loss-of-function mutation, but it confers a survival advantage in malaria-prone regions. The upshot of all this is that Darwin was right in believing that natural selection operating on random variations can cause organisms to become adapted to their environments, but he was wrong in believing that the process was constructive. Nowhere has the Darwinian mechanism been shown to build a complex system. It has only been shown to modify an already-existing system, usually in a loss-of-function manner. This is significant enough to upend the Darwinian narrative, but it gets worse. The same factors that contribute to adaptation work to prevent a species from evolving much further. Random mutation and natural selection quickly adjust species to their environmental niches, Behe writes, and then they maroon them there. He cites results from the long-running experiment conducted by Michigan State microbiologist Richard Lenski, whose E. coli lineage has surpassed 65,000 generations (equivalent to more than a million years for a large, complex species like humans), as sound evidence that random mutations wreak havoc in a species—and then that havoc gets frozen in place by natural selection. Behe sums up his main argument like this: “beneficial degradative mutations will rapidly, relentlessly, unavoidably, outcompete beneficial constructive mutations at every time and population scale.”1 The only Darwinian examples of evolution that have been observed have followed this pattern and resulted in evolutionary dead ends. Darwin devolves.,,,, https://salvomag.com/article/salvo49/darwinism-dissembled
Open access link to the full Thornton Lab paper: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9601886/ A lot to take in, even if you have some expertise in biochemistry. Alan Fox
A very good article. It is impossible, by chance, to produce useful, new function into anything if it does not fit in with the existing machinery. The assembly line example was very helpful and clear. It was easy to see robots arranged along a line, making parts for a car. The car door is not made to fit just anywhere on the car. It must attach to a specific place on the car. It has a specific function. Protein folds are complex. I have seen a three-dimensional view of a protein fold and it is complex and specific. It is obvious that it must end up folding in a particular way to function. It uses 'chaperones' to help it fold correctly. The final shape has a geometry that goes beyond molecular to subatomic. Evolution is not goal directed and to "upgrade" any organism requires a change that fits the existing machinery. The questions is: Where does the new information come from that upgrades any organism and adds useful function to it? There is no answer, just an assumption that some random mutation could create new, novel and useful information AND make sure, like the car door, that it is added to the machinery of the organism at the exact right place. Probability calculations show that evolution by random mutations cannot do this. relatd
A quote from Thornton's article: "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." If this is indeed true, then it seems that evolution actually does work! However, I question whether it is actually true in general. Two points: 1. Yes, any existing protein can be modified by a mutation, but what does that get you? If the mutation is neutral, you get essentially the same protein. If the mutation is not neutral, then you get a different amino-acid string, which most likely will not do anything useful. It is highly unlikely that you would get a new functional protein, much less a new, protein fold. Even if it had some new function, how could it work without fitting into the cell's pre-existing machinery? The cell would not "know" what to do with it, and it would just get in the way of normal operations. If it did fit into the existing cellular systems, then it would just be a tweak to an existing process; either redundant, less effective, or a new allele to the normal protein. In other words, just another small micro-evolution. 2. There is a lie in the last phrase. The "vast multidimensional landscape of ... amino acid sequences" is anything but "functional". It has been shown that typically only one in 10^74 random amino acid sequences long enough to be a protein candidate is likely to be functional - that is, doing something useful for the cell. Thus, evolving a new protein step by step is indeed a "long trek" through sequence wilderness (with no "natural selection guide) in order to find a new functional peak or oasis. It would be good to see serious examples demonstrating that "proteins can—and do—acquire new complex features by neutral processes". I did not read Thornton's article, but does the author provide examples or is he just assuming it is true? Basically, the author is claiming that the functional protein peaks in the vast sequence space are close enough together that it is simple to jump from one peak to another via a few easy mutations. This is the opposite of everything I've read on the subject. Fasteddious
Hi Otangelo Very nice article. The sequence problem is a killer issue for evolutionary theory. It turns out there are 3 other killer issues. -The waiting problem that Behe produced a peer reviewed paper on. I takes long periods of time for mutations to become fixed in a population. -The gene arrangement problem. Genes not generating a nested pattern among vertebrates primates etc. Some genes shared by humans and fish do not exist in mice in chickens -The chromosome count problem. Chromosome pairs do not follow a nested pattern that individual genes and morphological features generate It does look like the order in Genesis one is pretty accurate. bill cole

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