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So what are the lessons here?

- that structure is as/more important than sequence ?

- that "reaction centers" are what matter, and the rest is just "protection" ?

What do you mean by "reaction center" - surely not physically central within the folded structure (isn't it the surface shape that determines reactivity) ?

You are missing the point - sure a particular enzyme's function is resilent to large levels of substitution because:

1. The number of residues actively involved in catalysis might be small and 2. Most other residues can be safely replaced with something else either similar if part of the structure or anything if the side chain is pointing out on the surface.

However, the point the article is making is that for different functions the same basic folds seem to be used again and again.

Is that because the stable protein fold structural space is actually small ( due to the limited secondard structure patterns used etc ), or is that because evolution hasn't had time to to search the enormous available structural space?

ie is it a sampling problem or an instrinic property of protein space.

The fact that some of the ML approaches mentioned can now design completely novel folds suggests it is at least partially a sampling problem.

This to me isn't surprising - the idea that evolution is somehow complete and all possible solutions have already been explored seems to me to be unlikely - a lot of evolution happens via gene duplication and then gradual functional drift - which would favour reuse of existing folds over the generation of completely new ones.

And it seems very few proteins appear to be significant problems.

The most famous is the prion protein which can misfold in ways to cause a variety of contagious diseases. Like mad cow disease, chronic wasting disease, scrapie and in humans CJD and vCJD, fatal familial insomnia, Kuru, GSS.

Perhaps because misfoldings of the prion protein can convert others but why is it all affecting that same protein? Always baffled me why aren't other/many proteins suspitible to becoming a prion?

There are others we call "prionoid" because they can have shades of the catetrosphic misfolding prion can.

Evolution takes surprisingly little time to home in on solutions which are durable enough to handle local conditions. It's not demonstrably good at preparing its offspring for anything that would be useful outside the local environment. It also has a way of forgetting anything before the most recent data set (or global reset).

Our compute capacity isn't deployed to brute force Monte Carlo sims (mostly). So it's apples and oranges.

This reminds of the fact that certain fundamental proteins get created even if the DNA for them has errors.

The thinking is that evolution created error correction for the critical proteins to account for mutations.

Fascinating stuff.

> Natural selection has no analogy with any aspect of human behavior, However, if one wanted to play with a comparision, one would have to say natural selection does not work as an engineer works. It works like a tinkerer - a tinkerer who does not know exactly what he is going to produce but uses whatever he finds around him whether it be pieces of string, fragments or wood, or old cardboards; in short it works like a tinkerer who uses everything at his disposal to produce some kind of workable object.

―François Jacob, “Evolution and Tinkering” (https://web.mit.edu/~tkonkle/www/BrainEvolution/Meeting9/Jac...)

They found "several thousand" novel folds? I had remembered that there were around 1000:

https://pmc.ncbi.nlm.nih.gov/articles/PMC7072414/

Oh ok, I misremembered:

"This review has focused only on small fragments of fold space with examples given for folds generated from a single secondary structure string consisting of around ten SSEs. Even in this small corner, the number of possible folds, under the current constraints, is of the order of 1000"

What plagiarism even means in context of proteins? That one protein steals a fold of another protein without giving proper credit to it?

Agree... There should be some penalty to sites that want to show off their reports only to people with high end devices...

This is about folds, not amino acids - even if you used a larger alphabet of residues, I somehow doubt that you would get many more folds.

Thinking more about the question of protein _length_ - I'm also not convinced that longer proteins (more than say 750aa) would produce more novel folds. Larger proteins tend to be multi-domain; that is, a longer chain will fold into multiple compact domains, each one a separate fold.

I suppose there could be 'megafolds' out there in fold space, beyond 1000aa - like a 12-bladed beta propeller, or a beta-helix with alpha helices on the outside or some other wacky thing. Whether that would substantially increase the numbers of total folds, I doubt, but that is of course a guess.

(ref - https://pmc.ncbi.nlm.nih.gov/articles/PMC10251718/ for protein lengths)

> DNA and evolution, even with billions of years to think about it, is really a bit of a beginner when it comes to protein design.

I like how you say evolution is able to think when in reality it's just a mysterious function of variation, selection, and time.

The Unreasonable Annoyance of Cliches

But then, this thead is all about proteins incorporating structural cliches, isn't it?

I think it's a useful meme, as long as applied appropriately - where it truthfully promises some sort of surprise and potential insight.

It seems to have originated with Eugene Wigner's 1960 "The Unreasonable Effectiveness of Mathematics in the Natural Sciences".

At some point someone will analyze this pattern and post an article named "The Unreasonable effectiveness of the 'The Unreasonable X of Y' template".

Competing with "x is all you need"

This and "How I learned to stop worrying and love ___". I can't identify what grinds my gears so much about it, perhaps it's the laziness.