A Review Of The Case Against A Darwinian Origin Of Protein Folds By Douglas Axe, Bio-Complexity, Issue 1, pp. 1-12
By Robert Deyes
Proteins adopt a higher order structure (eg: alpha helices and beta sheets) that define their functional domains. Years ago Michael Denton and Craig Marshall reviewed this higher structural order in proteins and proposed that protein folding patterns could be classified into a finite number of discrete families whose construction might be constrained by a set of underlying natural laws (1). In his latest critique Biologic Institute molecular biologist Douglas Axe has raised the ever-pertinent question of whether Darwinian evolution can adequately explain the origins of protein structure folds given the vast search space of possible protein sequence combinations that exist for moderately large proteins, say 300 amino acids in length. To begin Axe introduces his readers to the sampling problem. That is, given the postulated maximum number of distinct physical events that could have occurred since the universe began (10exp150) we cannot surmise that evolution has had enough time to find the 10exp390 possible amino-acid combinations of a 300 amino acid long protein.
The battle cry often heard in response to this apparently insurmountable barricade is that even though probabilistic resources would not allow a blind search to stumble upon any given protein sequence, the chances of finding a particular protein function might be considerably better. Countering such a facile dismissal of reality, we find that proteins must meet very stringent sequence requirements if a given function is to be attained. And size is important. We find that enzymes, for example, are large in comparison to their substrates. Protein structuralists have demonstrably asserted that size is crucial for assuring the stability of protein architecture.
Axe has raised the bar of the discussion by pointing out that very often enzyme catalytic functions depend on more that just their core active sites. In fact enzymes almost invariably contain regions that prep, channel and orient their substrates, as well as a multiplicity of co-factors, in readiness for catalysis. Carbamoyl Phosphate Synthetase (CPS) and the Proton Translocating Synthase (PTS) stand out as favorites amongst molecular biologists for showing how enzyme complexes are capable of simultaneously coordinating such processes. Overall each of these complexes contains 1400-2000 amino acid residues distributed amongst several proteins all of which are required for activity.
Axe employs a relatively straightforward mathematical rationale for assessing the plausibility of finding novel protein functions through a Darwinian search. Using bacteria as his model system (chosen because of their relatively large population sizes) he shows how a culture of 10exp10 bacteria passing through 10exp4 generations per year over five billion years would produce a maximum of 5Ãƒâ€”10exp23 novel genotypes. This number represents the 'upper bound' on the number of new protein sequences since many of the differences in genotype would not generate "distinctly new proteins". Extending this further, novel protein functions requiring a 300 amino acid sequence (20exp300 possible sequences) could theoretically be achieved in 10exp366 different ways (20exp300/5Ãƒâ€”10exp23).
Ultimately we find that proteins do not tolerate this extraordinary level of "sequence indifference". High profile mutagenesis experiments of beta lactamases and bacterial ribonucleases have shown that functionality is decisively eradicated when a mere 10% of amino-acids are substituted in conservative regions of these proteins. A more in-depth breakdown of data from a beta lactamase domain and the enzyme chorismate mutase has further reinforced the pronouncement that very few protein sequences can actually perform a desired function; so few in fact that they are "far too rare to be found by random sampling".
But Axe's landslide evaluation does not end here. He further considers the possibility that disparate protein functions might share similar amino-acid identities and that therefore the jump between functions in sequence space might be realistically achievable through random searches. Sequence alignment studies between different protein domains do not support such an exit to the sampling problem. While the identification of a single amino acid conformational switch has been heralded in the peer-review literature as a convincing example of how changes in folding can occur with minimal adjustments to sequence, what we find is that the resulting conformational variants are unstable at physiological temperatures. Moreover such a change has only been achieved in vitro and most probably does not meet the rigorous demands for functionality that play out in a true biological context. What we also find is that there are 21 other amino-acid substitutions that must be in place before the conformational switch is observed.
Axe closes his compendious dismantling of protein evolution by exposing the shortcomings of modular assembly models that purport to explain the origin of new protein folds. The highly cooperative nature of structural folds in any given protein means that stable structures tend to form all at once at the domain (tertiary structure) level rather that at the fold (secondary structure) level of the protein. Context is everything. Indeed experiments have held up the assertion that binding interfaces between different forms of secondary structure are sequence dependent (ie: non-generic). Consequently a much anticipated "modular transportability of folds" between proteins is highly unlikely.
Metaphors are everything in scientific argumentation. And Axe's story of a random search for gem stones dispersed across a vast multi-level desert serves him well for illustrating the improbabilities of a Darwinian search for novel folds. Axe's own experience has shown that reticence towards accepting his probabilistic argument stems not from some non-scientific point of departure in what he has to say but from deeply held prejudices against the end point that naturally follows. Rather than a house of cards crumbling on slippery foundations, the case against the neo-Darwinian explanation is an edifice built on a firm substratum of scientific authenticity. So much so that critics of those who, like Axe, have stood firm in promulgating their case, better take note.
Read Axe's paper at: http://bio-complexity.org/ojs/index.php/main/article/view/BIO-C.2010.1
Michael Denton, Craig Marshall (2001), Laws of form revisited, Nature Volume 410, p.417
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