Functions are not so rare at all, and definitely not isolated, in sequence space of biopolymers

T-urf13 is an ion channel and evolved during selective breeding of maize.

The novel antimicrobial peptide discovered and described in Knopp et al 2019 is also an ion channel:
https://journals.asm.org/doi/full/10.1128/mBio.00837-19

Generally speaking transmembrane proteins are surprisingly easy to evolve, so much so that they are among the most likely de novo proteins.

The very weak sequence constraints on transmembrane domains has also been shown phylogenetically:
https://academic.oup.com/mbe/article/33/11/2874/2272007

Transmembrane domains are so easy to evolve because they’re essentially just repeat-proteins consisting of a single, simple structural element, such as a beta-hairpin. These will naturally tend to oligomerize, their hydrophobic exterior will have an intrinsic affinity for the hydrophobic interior of the membrane bilayer, and they form so-called “barrel” (essentially just tube-shaped structures).

(http://membranproteine.net/Structure%20gallery%201.html)

There is a lot of literature on the evolution of transmembrane repeat proteins (such as beta-barrel structures).

https://www.sciencedirect.com/science/article/pii/S0969212618302132

Etc. etc.

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I should add that I don’t think you’re wrong to say that some functions are more, or even considerably more rare, than others. I don’t think it would be sensible to extend the hyperabundance of some specific function in sequence space, to basically all protein functions. That would be an unwarranted extrapolation, and also doesn’t make biochemical sense.

But some functions being much more rare than others does not in and of itself imply they are too rare to evolve. It might imply they’re unlikely to evolve by de novo evolution from non-coding DNA, but there are other mechanisms available to evolution for novel gene evolution than that. I wrote a post about that here:

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I think each of those are likely enough, but their conjunction is probably considerably more unlikely in the same structure. If each function on it’s own has a probability of 10-9, back of the envelope estimate you get an overall probability of 10-27. That would make it quite hard to evolve from non-coding DNA, which is why things like shuffling of fragments, recombination among sub-domains structures, and gene-fusion are very important in evolution, which is why work like this is very relevant and important to this question:

https://academic.oup.com/mbe/article/38/6/2191/6120801

Oh sure, absolutely. Then again, each of those individual functions (potentially) has intrinsic utility to an organism, especially an organism that didn’t have a system with all three together. Which helps explain where you got the material for those recombinations.

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Only if you keep in mind that binding is the essence of catalysis, which is very basic biochemistry. That’s why we can immunize mice with a substrate, with the immune system selecting ONLY for binding, and end up with catalytic antibodies.

Myosins are among the best-studied and most complex proteins known.

Why is human beta-cardiac myosin so polymorphic, while the obviously less-complex actin is not at all, Gil?

This shows that @gpuccio’s notion that sequence conservation represents functional complexity is absurd.

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You are on the path to enlightenment here.

Binding is pervasive in biochemistry. Bonds - ionic bonds, covalent bonds, hydrogen bonds, van der Waals interactions - binding electrons, binding simple diatomic molecules, and binding gigantic biomolecules. We have tracked while SARS-CoV-2 synergistically enhanced its binding to ace2 receptors through multiple mutations; with lethal effect for contagion and virulence. The same mutations have independently occurred in multiple strains, so the function in sequence space could not be so rare. Influenza virus normally uses hemagglutinin for cell entry and neuraminidase for egress, but the virus has been observed to mutate neuraminidase to resourcefully achieve receptor binding in place of hemagglutinin.

Not so different. DNA polymerases and ligand-gated ion channel channels involve binding.

A great deal of our body’s homeostasis involves binding. Binding by one molecule can change the shape of the bound molecule, causing the release or binding of yet another molecule. Extensive feedback loops function by complex cascades of binding. Nature is always fiddling with the electrostatic shapes of biomolecules, and while complexity is not a goal it is often a result. Indeed, it isn’t at all surprising that the proteins which perform the functions which sustain life are not so rare.

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The bindings involve in complex functional proteins such as DNA polymerases or ligand-gated ion channels are not mere unspecified bindings, but highly fine tuned, integrated, coordinated and regulated bindings which can only be established within large proteins exhibiting high functional information.

Your second sentence doesn’t follow from your first one, quite the contrary.

But that second sentence is well supported, if you look at the scientific literature.

A paper that found that 8000 mutants of DNA polymerase MOTIF A ALONE (that is, only the 13 amino acid functional site) were functional, most of which had activity similar to the wild type; They found only ONE of the 13 amino acid was required to stay the same.

There would be so many more functional mutants if they mutated other parts of the enzyme.

The enzyme active site, is probably the part that can vary LEAST.

https://www.researchgate.net/publication/248529063_Conservation_and_mutability_in_molecular_evolution

For example, if we extrapolated 8000 functional sequences from varying the core 13 AAs to the rest of 130 AA protein, then there would be 8000^10 functional variants.

There are likely more than 8000^10 (ie, 10^39) 130AA functional variants of DNA polymerase A. And of course, more if you allow the number of AAs vary.

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The Patel and Loeb source paper here.

It would appear that a high degree of optimization and conservation does not infer brittleness of functionality. See also:

Do you consider the spike mutations of the SARS-CoV-2 delta variant to be a “mere unspecified binding”, or a “highly fine tuned, integrated, coordinated and regulated bindings which can only be established within large proteins exhibiting high functional information.”?

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If it’s that fine tuned, how was it that my colleagues and I could change the specificity of two of the most complex proteins known (myosins) without a significant effect on their normal functions, merely by changing a single amino-acid residue in the active site to one not found in nature?

If you are correct, we could not possibly have succeeded. Link to 5 papers below:

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Just as there are immensely more ways to lose a lottery than to win it.

Therefore, lotteries are never won.

Do you agree with that conclusion?

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Yet that’s precisely what we varied in the papers linked to above. Not merely in the active site, but a tyrosine residue whose side chain is all but contacting the substrate, ATP.

Gil’s claims are utterly falsified by our work.

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Well that whole thing with “highly fine tuned, integrated, coodinated and regulated bindings”, with “high functional information” sure sounds complicated, but none of that constitute evidence or an argument that enzymes or ligand-gated ion channels are unevolvable, which is still just a baseless axiom no evidence supports.

We’ve already seen evidence that has basically convinced every expert in the field that membrane channels are rather easy to evolve, and there’s an enormous amount of evidence that new enzymes can evolve by processes described in previous posts.

More rare functions generally evolve from more frequent functions. Pieces of already existing proteins are recombined, shuffled, and fused together into new proteins, so a completely random sampling of sequence space doesn’t have to occur, rather the search is intrinsically biased to things much closer in sequence space to other functional things.

The tornado in a junkyard is a strawman, and the putative isolation of functions is a fantasy.

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/fnord

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So, Gil, shall we go through these papers together?

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