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Are Proteins Attracted to Function?

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Douglas Axe
Photo: Douglas Axe.

Doug Axe showed that functional space is a tiny fraction of sequence space in proteins. Evolutionists think they found a shortcut as simple as dropping down a funnel. Proteins don’t have to search all of sequence space at random; a “ring attractor” pulls them down the thermodynamic funnel into functional glory land.

Richard Dawkins has been criticized for years now for his “Weasel” analogy (see Jonathan Witt’s critique). And yet the myth lives on. Miracles happen with the words, “It evolves!” while waving the magic wand, Natural Selection. Here’s a new instance involving protein folds.

“Methinks It Is Like a Weasel”

Dawkins’s main error was with setting a target sequence for random letters (the Hamlet sequence “Methinks it is like a weasel”), and then preserving the randomly changing letters that matched the target. Natural selection as Darwin envisioned it has no target sequence. Each step must be functional, or it is not selected. All the intermediate phrases in Dawkins’s computer simulation were gibberish. They had no function in language. They would never converge on the target phrase by unguided natural processes. 

The same is true with random sequences of amino acids, called polypeptides. They have no function and are not called proteins or enzymes unless and until they fold into a functional shape. Before considering the following hypothesis by two chemists, remember that without guidance from genes, polypeptides fall into the vast neverland called “sequence space” where nothing happens (the amino acids, furthermore, must be left-handed, or homochiral). “Functional space” is but a tiny fraction of sequence space. Doug Axe discussed this in his book Undeniable, based on his own research at Cambridge. He experimentally determined how much change was necessary to break a functional protein with mutations. It led to his estimate that a random polypeptide 150 amino acids in length, which is modest for a protein, has only a 1 in 1074 chance of arriving at a functional fold. That probability drops to an impossible 1 in 10148 chance if the sequence must be homochiral, and even lower if the sequence also has to consist of only peptide bonds. In short, it would be a miracle.

A Shortcut to the Miraculous

In their paper in PNAS, “Funneled energy landscape unifies principles of protein binding and evolution,” Zhiqiang Yan and Jin Wang think they have found a shortcut to the miraculous. Natural selection will push the polypeptide down a thermodynamic funnel, like a golfer putting a ball into the cup. Why? Because, clearly, proteins “have evolved.” Anything that has evolved would have had the magic wand of natural selection to do the magic. 

Most proteins have evolved to spontaneously fold into native structure and specifically bind with their partners for the purpose of fulfilling biological functions. According to Darwin, protein sequences evolve through random mutations, and only the fittest survives. The understanding of how the evolutionary selection sculpts the interaction patterns for both biomolecular folding and binding is still challenging. In this study, we incorporated the constraint of functional binding into the selection fitness based on the principle of minimal frustration for the underlying biomolecular interactions. Thermodynamic stability and kinetic accessibility were derived and quantified from a global funneled energy landscape that satisfies the requirements of both the folding into the stable structure and binding with the specific partner. The evolution proceeds via a bowl-like evolution energy landscape in the sequence space with a closed-ring attractor at the bottom. The sequence space is increasingly reduced until this ring attractor is reached. The molecular-interaction patterns responsible for folding and binding are identified from the evolved sequences, respectively. The residual positions participating in the interactions responsible for folding are highly conserved and maintain the hydrophobic core under additional evolutionary constraints of functional binding. The positions responsible for binding constitute a distributed network via coupling conservations that determine the specificity of binding with the partner. This work unifies the principles of protein binding and evolution under minimal frustration and sheds light on the evolutionary design of proteins for functions. [Emphasis added.]

Methinks these are weasel words. This is like the following syllogism. Major premise: Everything evolves by natural selection. Minor premise: Proteins occupy a tiny fraction of sequence space that permits folding and binding to specific partners. Conclusion: Natural selection pushed proteins to fulfill these constraints. Anything circular here? What if one does not accept the major premise? 

To make their point, Yan and Wang know that they have to satisfy the laws of thermodynamics, which militate against functional folds by accident. Sure enough, the paper has lovely equations. But if the premise is wrong, equations only provide window dressing on a fake storefront. Here is the weasel-like target sequence:

To realize the principle of minimal frustration in protein evolution, one of the typical naturally occurring protein domains (WW domain) and its binding complex were chosen as the evolution model. WW domains preferably bind Pro-rich peptide. The native structure of the binding complex … was considered as the evolved and functional structures (SI Appendix, Fig. S2). The evolution simulation is to mimic how nature selects and optimizes the sequences of the WW domain, which can spontaneously fold and preferably bind to the specific Pro-rich peptide.

Their “principle of minimal frustration” refers to optimization of protein sequences. The principle is useful for analyzing proteins, but not for accounting how they became optimized.

The principle of minimal frustration has been fruitful in illustrating how the global pattern of interactions determines thermodynamic stability and kinetic accessibility of protein folding and binding. The principle requires that energetic conflicts are minimized in folded native states, so that a sequence can spontaneously fold. Because of the functional necessity, naturally occurring sequences are actually in the tradeoff for coding the capacity to simultaneously satisfy stable folding and functional binding. From the view of localized frustration, naturally occurring proteins maintain a conserved network of minimally frustrated interactions at the hydrophobic core. In contrast, highly frustrated interactions tend to be clustered on the surface, often near binding sites that become less frustrated upon binding. A natural question is how the evolution sculpts the interaction patterns that conflict with the overall folding of minimal frustration but are specific for protein binding.

An Intelligent Design Principle

This principle is an ID principle: proteins are sculpted to have stable cores, but flexible surfaces. They are optimized for this. To make evolution the sculptor begs the question. It’s like saying, “proteins must fulfill requirements for thermodynamic stability and kinetic accessibility; therefore, evolution fulfilled these requirements.” It’s like saying, “We take minimal frustration to be a measure of fitness, and since natural selection always moves toward higher fitness, proteins evolved the observed optimization.” How do they not recognize the circular reasoning here? They are following a principle of maximal frustration for critical thinkers! It’s incredible that this kind of circular argument was published in the premiere journal of the National Academy of Sciences and survived the editing scrutiny of David A. Weitz of Harvard.

Protein function is the ultimate goal of protein evolution via mutagenesis for survival. This work has proposed and quantified the selection fitness of protein evolution with the principle of minimal frustration. The selection fitness of thermodynamic stability and kinetic accessibility incorporates both folding and binding requirements. Driven by the selection fitness, the evolution dynamics in sequence space can be depicted and visualized as a bowl-like energy landscape where the sequence space is increasingly reduced until the closed-ring attractor is reached at the bottom. The evolved sequences located in the basin of the attractor faithfully reproduce the interaction patterns as those extracted from naturally occurring sequences…. The consistency validates the principle of minimal frustration as the selection fitness of protein evolution. To fulfill the folding and function, evolution sculpts the interaction patterns with the minimal-frustration principle to develop the hydrophobic core for folding and the coupling network for functional binding.

Comparing this to Dawkins Weaselology, this is like saying, “The goal of sentences is to express meaning. Driven by this selection fitness, evolution dynamics guarantee that random letters will fall through a bowl-like semantics landscape where the randomness is reduced until a closed ring of meaningful sentences naturally occurs. The fact that natural sentences convey meaning validates this principle. Evolution sculpts meaning from random letters because it must, and lo and behold, it does.” Aaagggh! How does this notion pass peer review?

Making Circularity Practical

To make their circularity seem practical, they show what else could be done by reasoning in a circle in the wide-angle view:

In addition, the evolution of a protein binding/assembling system generally involves the evolution of each binding/assembling partner. Therefore, the evolution of one partner is constrained or coupled to the evolution of its partners, i.e., coevolution of the partners, such as a toxin–antitoxin system. In this case, the selection fitness of protein evolution involves the constraints not only from its own folding and binding but also from those of its partners. The study of this more complex issue would bridge the evolution of a single protein to the evolution of a protein network.

The whole world is circular. Isn’t that a useful idea!

A Preprint with Similar Fallacies

This kind of reasoning is not limited to this paper. Five authors, including Joseph W. Thornton (whom Michael Behe says threw a “monkey wrench” into Darwinian evolution), wrote a preprint on bioRxiv with similar fallacies. In “Chance, contingency, and necessity in the experimental evolution of ancestral proteins,” they assert that varieties of BCL-2 (an anti-apoptosis protein) arrived at their optimum fitness by convergent evolution, even though they recognize that there was no way to expect that because of the inevitability of chance and contingency in unguided natural processes:

Finally, our observations suggest that the sequence-structure-function associations apparent in sequence alignments are, to a significant degree, the result of shared but contingent constraints that were produced by chance events during history. Present-day proteins are physical anecdotes of a particular history: they reflect the interaction of accumulated chance events during descent from common ancestors with necessity imposed by physics, chemistry and natural selection. Apparent “design principles” in extant or evolved proteins express not how things must be — or even how they would be best — but rather the contingent legacy of the constraints and opportunities that those molecules just happen to have inherited.

Once again, they treat natural selection as a sculptor with a guiding hand. The constraints to get sequences that work must have chosen working products out of the vast sea of possibilities. They evolved because they evolved. They look designed, but the “design principles” are only apparent. 

Dawkins would be pleased that his fallacy continues to be fruitful. His critics worry about the overpopulation of weasels in science. Hawks, flying overhead the infested area, casting a wide view over the creatures running in circles, make good weasel predators.