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The Unreasonable Redundancy of Nature's Protein Folds
- hirenj 4mo agoThis 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 https://www.science.org/doi/10.1126/science.adq4946
- jeejay1 4mo agoWhat plagiarism even means in context of proteins? That one protein steals a fold of another protein without giving proper credit to it?
- gilleain 4mo agoI 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.
- hirenj 4mo agoYes, 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 “accessible” limit?
- gilleain 4mo agoI 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) 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.
- pfdietz 4mo agoIt could also mean "evolutionarily accessible". The basin of attraction in sequence space has to be sufficiently large that evolution could stumble across it.
- jeejay1 4mo agoDo you have an example of such sequences in mind? Because I can’t recall any example.
- gilleain 4mo agoA very reasonable question, that I don't have an immediate concrete answer to! Apparently I upvoted this question in the past (found it by searching for an answer - no AI, like the good old days) https://biology.stackexchange.com/questions/2507/are-there-any-examples-of-proteins-with-no-or-minimal-sequence-identity-but-hig https://biology.stackexchange.com/questions/2507/are-there-a... One answer mentions actin and hexokinase. I'm not familiar with the actin fold, but looks like a bab sandwich of some kind. Another commenter on this page mentioned the 'Rossman fold', another classic, and TIM barrels also occur to me. One caution is that some of these I would consider higher-level patterns - the 'Topology' level of CATH hierarchy. Naturally, the more high-level (abstract) the fold pattern, the larger the sequence space it covers. It is less interesting to say that a helical bundle (for example) covers a lot of diverse sequences.
- gilleain 4mo agoThey found "several thousand" novel folds? I had remembered that there were around 1000: https://pmc.ncbi.nlm.nih.gov/articles/PMC7072414/ 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"
- hirenj 4mo agoI think there was a Twitter/Bluesky thread on the results from adding all the predicted folds from metagenomics too, and not ending up with many new clusters. If this continues to hold true as we keep looking at stuff, I will be relieved that at least natural protein folds and domains has a limited (tractable) solution space. All we need to do now is annotate the variation of these couple of thousands of fold variants. Challenging, but at least a bounded problem.
- flobosg 4mo ago> 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/Jacob%201977%20Science.pdf https://web.mit.edu/~tkonkle/www/BrainEvolution/Meeting9/Jac...)
- canadiantim 4mo agoTinker tailor fold or die?
- h_a_n_k 4mo agocool post! it's funny how many things in this world are naturally graphs. i think it's neat how, especially in biology, a lot of high-dimensional objects, like protien sequences, converge onto lower-dimensional representations, like protein structures. 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
- throwaway81523 4mo agoThis crashed my browser. Use reader mode.
- ifh-hn 4mo agoNo real clue what this stuff is about, way over my head, but kudos on an article where it's all there on the page instead of needing scripts to pull text and images from different places!
- resiros 4mo agoEvolution 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.
- noduerme 4mo agoEvolution 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.
- alexpotato 4mo agoThis 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.
- rustyhancock 4mo agoAnd 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.
- spwa4 4mo agoThis 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.
- gilleain 4mo agoThis 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/ https://pmc.ncbi.nlm.nih.gov/articles/PMC10251718/ for protein lengths)
- spwa4 4mo agoAmino 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.
- novia 4mo agogosh the scrolling on that site was so jumpy!
- omnifischer 4mo agoAgree... There should be some penalty to sites that want to show off their reports only to people with high end devices...
- jyounker 4mo agoNone 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.]
- HarHarVeryFunny 4mo agoSo 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) ?
- flobosg 4mo ago> that structure is as/more important than sequence? 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.
- Schlagbohrer 4mo agoCan we please retire the headline trend of "The Unreasonable ___ of ____ "
- bl0rg 4mo agoAt some point someone will analyze this pattern and post an article named "The Unreasonable effectiveness of the 'The Unreasonable X of Y' template".
- tux3 4mo agoEverything old is new again! We've had "Go To Statement Considered Harmful" Considered Harmful [1]. 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.purdue.edu/ParaMount/papers/rubin87goto.pdf https://web.archive.org/web/20090320002214/http://www.ecn.pu...
- ramraj07 4mo agoCompeting with "x is all you need"
- HarHarVeryFunny 4mo agoI 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".
- flobosg 4mo agoMy PhD thesis addressed a similar question. I did a survey of sub-domain sized fragments shared between different protein folds. It turns out that there are plenty, even among folds considered evolutionarily distant.
- dekhn 4mo agoProteins are truly amazing. I've studied them for decades and they still manage to surprise; for example, i worked with protein structural prediction for decades and assumed that structure was necessary for function, but some proteins remain mostly unfolded and still carry out complex mechanistic tasks.
- dekhn 4mo agoI worked with a foodie who was also a protein scientist (https://scienceandfooducla.wordpress.com/2016/02/23/kent-kirshenbaum/ https://scienceandfooducla.wordpress.com/2016/02/23/kent-kir...) and he once pointed out: nearly everything you need to know about protein folding, you can learn from an egg.
- nickpsecurity 4mo agoHow so?
- photochemsyn 4mo agoThis does reveal the weakness of AlphaFold approaches for answering questions like “what is possible in the protein folding space if you use the 20 canonical amino acids” since the data used to train AlphaFold is limited to existing experimentally determined protein structures. 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/ https://pmc.ncbi.nlm.nih.gov/articles/PMC10296201/ “Non-Canonical Amino Acids as Building Blocks for Peptidomimetics: Structure, Function, and Applications” (2023)
- flobosg 4mo ago> since the data used to train AlphaFold is limited to existing experimentally determined protein structures Protein sequences, but the point still stands.