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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

#41

Post by DrScientist »

jyounker wrote: post #19

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 rep…

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.

Re: The Unreasonable Redundancy of Nature's Protein Folds

#42

Post by [deleted] »

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…

[deleted]

Re: The Unreasonable Redundancy of Nature's Protein Folds

#43

Post by alexpotato »

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…

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.

Re: The Unreasonable Redundancy of Nature's Protein Folds

#44

Post by IAmBroom »

suncemoje wrote: post #32
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…

> 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.

I find it completely daunting to speak of evolutions processes without some anthropomorphism sneaking in, despite being a hardcore atheist.

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..."

Re: The Unreasonable Redundancy of Nature's Protein Folds

#45

Post by dekhn »

Proteins 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.

Re: The Unreasonable Redundancy of Nature's Protein Folds

#46

Post by resiros »

DrScientist wrote: post #41
jyounker wrote: post #19

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 rep…

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 differ…

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

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.

Re: The Unreasonable Redundancy of Nature's Protein Folds

#47

Post by rustyhancock »

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…

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.

Re: The Unreasonable Redundancy of Nature's Protein Folds

#49

Post by Windchaser »

DrScientist wrote: post #41
jyounker wrote: post #19

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 rep…

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 differ…

It seems just obvious that it's at least a sampling problem. Assuming an average protein length of 400 amino acids and 20 possible amino acids, that's about 10^520 different possibilities for sequences, which is a mind-bogglingly large number.

We haven't even begun to explore the biological universe.

Re: The Unreasonable Redundancy of Nature's Protein Folds

#50

Post by photochemsyn »

This 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/

“Non-Canonical Amino Acids as Building Blocks for Peptidomimetics: Structure, Function, and Applications” (2023)

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