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The Unreasonable Redundancy of Nature's Protein Folds

research.ligo.bio

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Re: The Unreasonable Redundancy of Nature's Protein Folds

#11

Post by resiros »

Evolution discovered a bunch of structural patterns at different layers (fragments, folds..) that are energetically favorable, versatile, easily foldable, robust to mutations and then kept reusing them. As a result it sampled more and more in these parts of the space. That's why the fold space is uneven.

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.

Re: The Unreasonable Redundancy of Nature's Protein Folds

#12

Post by spwa4 »

This is just repeating the fact that the proteins life actually uses are a very small part of the total possible ones. First, there's no real length limit, but all life's proteins are limited to a few thousand amino acids. Most barely get past hundred.

(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.

Re: The Unreasonable Redundancy of Nature's Protein Folds

#14

Post by gilleain »

spwa4 wrote: post #12

This is just repeating the fact that the proteins life actually uses are a very small part of the total possible ones. First, there's no real length limit, but all life's proteins are limited to a few thousand amino acids. Most barely get past hundred. (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 build…

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)

Re: The Unreasonable Redundancy of Nature's Protein Folds

#15

Post by spwa4 »

gilleain wrote: post #14
spwa4 wrote: post #12

This is just repeating the fact that the proteins life actually uses are a very small part of the total possible ones. First, there's no real length limit, but all life's proteins are limited to a few thousand amino acids. Most barely get past hundred. (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 build…

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 fo…

Amino acid (sequence) defines the folds.

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.

Re: The Unreasonable Redundancy of Nature's Protein Folds

#16

Post by noduerme »

resiros wrote: post #11

Evolution discovered a bunch of structural patterns at different layers (fragments, folds..) that are energetically favorable, versatile, easily foldable, robust to mutations and then kept reusing them. As a result it sampled more and more in these parts of the space. That's why the fold space is uneven. Are there any folds and patterns that evolution evolution has not discovered that are also useful? I think Baker G…

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.

Re: The Unreasonable Redundancy of Nature's Protein Folds

#17

Post by gilleain »

hirenj wrote: post #10
gilleain wrote: post #8

Earlier quoted context omitted.

I understood it as metaphor - just that evolutionarily distant sequences can adopt the same (or very similar) folds because there are only a limited number of stable, accessible folds that are possible.

Yes, that is exactly what I meant! Here’s an experiment to try: Frances Arnold got a nobel prize for work related to directed evolution. However, we know evolution is limited by the tools available to it as you mention. If we add random chaperones and co-factors to bacteria that we know other organisms use, can we push evolution outside of the known fold space? Is the limited fold space an absolute limit or the “acce…

I see. I meant 'energetically accessible', but you mean more like 'affordably accessible' (in the sense that the molecular toolkit of a cell is what can 'afford' certain structures, due to chaperones available and so on).

Who knows what might be possible if you designed a cell from scratch - perhaps you could rework all the machinery to access other parts of fold space. After all, there are some weird and wonderful machines out there like the 'Vault' (https://en.wikipedia.org/wiki/Vault_(organelle)) that can fit whole proteins inside them. Possibly a different cage-like structure could help fold designed proteins into as-before unseen structures.

Re: The Unreasonable Redundancy of Nature's Protein Folds

#18

Post by gilleain »

spwa4 wrote: post #15
gilleain wrote: post #14

Earlier quoted context omitted.

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 fo…

Amino acid (sequence) defines the folds. 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…

A random sequence may not fold at all! I seem to remember a paper that tried this, creating a bunch of random proteins, and checking how much structure they had - I think they were helical bundles, but don't quote me.

The nice thing about stable folds, is that 'nearby' sequences in sequence space - as in, point mutations - are the same fold. If each sequence had a completely different fold, then mutation would be much more destructive. Surprisingly, however, sequences that are far apart in sequence space can also adopt the same fold (convergent evolution).

Re: The Unreasonable Redundancy of Nature's Protein Folds

#19

Post by jyounker »

None of this seems particularly surprising to someone who was an undergraduate level of biochemistry knowledge. Thirty years ago the professor in my Proteins class made a few relevant important points in his lectures:

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.]

Re: The Unreasonable Redundancy of Nature's Protein Folds

#20

Post by flobosg »

hirenj wrote: post #2

This approach is pretty much like the TED approach from a few years back. As far as I remember there wasn’t a ridiculous amount of fold diversity there either. It turns out evolution isn’t averse to a bit of liberal protein plagiarism. https://www.science.org/doi/10.1126/science.adq4946

> 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...)

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