1) Only handful of amino acids in a enzyme structures were highly conserved. (Out of hundreds, generally less than ten.)
2) Those were generally in the reaction center.
3) Almost all single sequence replacements had no measurable effect on protein structure and function.
4) Across species the "same" protein can diverge in sequence by up to 40%, while keeping the same structure. Sometimes this goes as far as 80%.
Given these basic facts, the findings in the paper aren't really surprising to anyone who studies proteins.
[Note: As with everything in biology, you can find counter examples. The histone proteins involved in DNA packing have an incredibly conserved sequence.]
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.
The result also fits in with the rest of biochemistry. While there are a vast variety of interesting chemicals in living things, and they do all sorts of amazing stuff, there are really only a handful of classes of chemicals.
The variety of classes of chemicals that can exist dwarfs what gets used in biochemistry. Why would we expect structure to be different?
We're in agreement though, that it would be interesting to understand what the constraints are.
That's a basic fact in bio. Check the rossman fold page for example: https://en.wikipedia.org/wiki/Rossmann_fold it's a template used for many functions.
We haven't even begun to explore the biological universe.
- 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) ?
Structure is determined by sequence, so they are equally important. Structure is more conserved than sequence, mainly due to the physicochemical constraints that govern protein folding.
> that "reaction centers" are what matter, and the rest is just "protection"?
Sometimes not even protection. Many enzymes can have plenty of its sequence/structure removed and still be functional. Natural proteins carry lots of evolutionary cruft.
> What do you mean by "reaction center" - surely not physically central within the folded structure
I think they borrowed the term from photosystems/photosynthesis. But, to be more precise, what they actually meant is the active site of an enzyme; the location where the catalyzed reaction takes place.
> (isn't it the surface shape that determines reactivity) ?
Shape is not enough, the chemical nature of the amino acid residues involved is also important. A single mutation in a key catalytic residue will shut down the enzyme even if the shape stays the same.
An enzymatic reaction center is also known as an "active size". It's the location within an enzyme's 3D structure where catalysis happens.
The only lesson is that, to a biochemist, the result is not surprising.
―François Jacob, “Evolution and Tinkering” (https://web.mit.edu/~tkonkle/www/BrainEvolution/Meeting9/Jac...)
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"
It seems to have originated with Eugene Wigner's 1960 "The Unreasonable Effectiveness of Mathematics in the Natural Sciences".
Now it's the Unreasonable Effectiveness of "The Unreasonable Effectiveness of X".
It seems like "X is All You Need" is All You Need.
[1]: https://web.archive.org/web/20090320002214/http://www.ecn.pu...
But then, this thead is all about proteins incorporating structural cliches, isn't it?
(note: there are bigger proteins, including ones so big you can see them with the naked eye (e.g. a hair) but they consists of multiple repeats of the same small building block. There are many such building blocks. And the very few exceptions to that are "not really" part of eukaryot cells, but of cell organelles that have their own DNA)
But even if you just take the first 4 amino acids, there's half a million possible combinations. Life uses less than 1000 of those.
In other words: 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. Or at least, it is pretty obvious that it's possible to do A LOT better than natural selection.
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)
And really? Just any random sequence gets you a new fold. I mean, it won't be very useful if you pick a random one, but it'll work and be a new one.
I think this is just an artifact of natural selection basing new proteins on existing ones, not an actual useful ("rational" if you can call natural selection rational) selection limit. I don't think that if you designed proteins from first principles you'd see this limitation in your results.
I like how you say evolution is able to think when in reality it's just a mysterious function of variation, selection, and time.
It's all so complex, and our verbs that more literally describe the billions of nanosecond operations going on in the cells feel inadequate. "When a protein molecule in an appropriate folded shape and orientation happens to be bounced by kinetic energy into the attractive region of a corresponding protease..." versus "The protease grabs the protein and cuts it into..."
Are there any folds and patterns that evolution evolution has not discovered that are also useful? I think Baker Group created a bunch of new folds. I'm not sure if they are as useful as the one discovered by Evolution. After all, Evolution had more compute power than us.
Our compute capacity isn't deployed to brute force Monte Carlo sims (mostly). So it's apples and oranges.
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.
The thinking is that evolution created error correction for the critical proteins to account for mutations.
Fascinating stuff.
We don’t even know if this is like body plans (four legs for mammals, why not six?) i.e. is this about physical limitations of the folding space (did evolution explore most of the space and hold onto the most useful folds, or are the common set of folds one of those accident-of-history results?). Then there’s the issue that folding takes place as the protein chain exits the ribosomal tunnel so that’s a whole other constraint on what kinds of folds might be selected. For that matter, why not other genetically determined complex amino acids instead of just the canonical set?
Also, a common evolutionary process in eukaryotes is duplication of protein sequences and shuffling of code blocks which might represent folding domains, which might tend to lock in the existing collection of folds rather than generating novel folds. That’s not so clear.
This weakness of AlphaFold has some modern practical relevance since non-canonical amino acids and modified proteins are increasingly used medically, and their structures mostly seem to be determined using the direct experimental methods, eg:
https://pmc.ncbi.nlm.nih.gov/articles/PMC10296201/
“Non-Canonical Amino Acids as Building Blocks for Peptidomimetics: Structure, Function, and Applications” (2023)
Protein sequences, but the point still stands.
i did neuroscience for grad school, and i was always amazed by how often complex neural activity could be well represented by lower dimensional representations--clean manifolds, attractor dynamics, etc. i think, in general, biology (evolution) doesn't penalize against redundancy too hard (hence things like genetic drift, neutral theory of evolution, etc.).
anyway, super cool stuff. agree with you that probs more useful to explore the search space via 'less natural' structures, given how forgiving evolution is to redundancy. probs where the most information can be found
