Extremely interesting lecture on protein evolution by Dan Tawfik

The late protein biochemist Dan Tawfik(died recently in a mountain climbing accident) did this extremely interesting lecture back in 2020, on his research group’s work on very early protein evolution:

Highly worth watching for anyone else interested in this subject of protein evolution. And highly relevant to the question of the origin of enzymes.

He talks about attempts to reconstruct the earliest stages in the emergence of enzymes from short peptide sequences, what functions they might have had before they worked as catalysts, how they assemble into larger tertiary and quaternary structures, and later evolved into more complex and folding protein structures with bona fide enzymatic activities.

Of particular interest (at least to me) is what he says starting at about 13:48, where he explains how phosphate binding seems to have evolved about 300 times independently in the history of life. And yet the method of phosphate binding in proteins is radically different between late (post-LUCA) proteins, and pre-LUCA proteins. Only in pre-LUCA proteins, which are all core metabolic enzymes, is phosphate bound by the least efficient method of phosphate binding. But it its nevertheless the only type of phosphate binding allowed by small peptides, and which are constructed of the so-called “pre-biotic” amino acid alphabet that didn’t have the later evolved aromatic amino acids.

So at the emergence of the first enzymes, the constraints on their size and amino acid alphabet only allowed a particular and very inefficient method of phosphate binding, and that is why the oldest core metabolic enzymes all share that unique method of binding. It seems to me this too is evidence for evolution and a natural origin of life. Think about it.

Another question that comes up (and which have been discussed here) is whether mere ligand binding could have conferred biologically meaningful functions. Turns out it can. ProffessorTawfik’s colleagues published this article after his death, on the latest work he was doing trying to answer exactly such questions as how mere ligand binding can serve meaningful biological functions:

Noor, E, Flamholz, AI, Jayaraman, V, Ross, BL, Cohen, Y, Patrick, WM, et al. Uniform binding and negative catalysis at the origin of enzymes. Protein Science . 2022; 31( 8):e4381. https://doi.org/10.1002/pro.4381

Abstract

Enzymes are well known for their catalytic abilities, some even reaching “catalytic perfection” in the sense that the reaction they catalyze has reached the physical bound of the diffusion rate. However, our growing understanding of enzyme superfamilies has revealed that only some share a catalytic chemistry while others share a substrate-handle binding motif, for example, for a particular phosphate group. This suggests that some families emerged through a “substrate-handle-binding-first” mechanism (“binding-first” for brevity) instead of “chemistry-first” and we are, therefore, left to wonder what the role of non-catalytic binders might have been during enzyme evolution. In the last of their eight seminal, back-to-back articles from 1976, John Albery and Jeremy Knowles addressed the question of enzyme evolution by arguing that the simplest mode of enzyme evolution is what they defined as “uniform binding” (parallel stabilization of all enzyme-bound states to the same degree). Indeed, we show that a uniform-binding proto-catalyst can accelerate a reaction, but only when catalysis is already present, that is, when the transition state is already stabilized to some degree. Thus, we sought an alternative explanation for the cases where substrate-handle-binding preceded any involvement of a catalyst. We find that evolutionary starting points that exhibit negative catalysis can redirect the reaction’s course to a preferred product without need for rate acceleration or product release; that is, if they do not stabilize, or even destabilize, the transition state corresponding to an undesired product. Such a mechanism might explain the emergence of “binding-first” enzyme families like the aldolase superfamily.

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Interesting. I have also seen this recent presentation.

[Mod note: It’s a long video, get comfortable.]

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Also very interesting. And again we see examples of folding proteins evolving from short peptide sequences that are capable of forming higher order structures through oligomerization. Goes together well with the paper I wrote about in this thread:

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