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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

#51

Post by flobosg »

photochemsyn wrote: post #50

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 sp…

> since the data used to train AlphaFold is limited to existing experimentally determined protein structures

Protein sequences, but the point still stands.

Re: The Unreasonable Redundancy of Nature's Protein Folds

#52

Post by flobosg »

resiros wrote: post #46
DrScientist wrote: post #41

Earlier quoted context omitted.

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.

Same with the TIM barrel fold. It can catalyze a wide range of reactions.

Re: The Unreasonable Redundancy of Nature's Protein Folds

#53

Post by DrScientist »

Windchaser wrote: post #49
DrScientist wrote: post #41

Earlier quoted context omitted.

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.

Sure - though because of the functional overlap of amino acids already discussed the functional/structural space could be a lot smaller ( though still massive ) - ie is choosing D or E at a particular position "different" in most situations?

And if you take it up a level of abstraction and say there are 4 ( ish ) basic types of secondary structure ( helix, turn, sheet, disordered ). Then you could argue the structural space is even smaller still.

Or put it another way if you can have sequences with 30% identity or lower with the same fold - that's a awful lot of different unique combinations that collapse into a single structural space.

And on the flip side - what we don't know is what percentage of sequence space don't actually result in a functional fold - ie results in instability and multiple stable or unstable conformations.

So it could be we are close to all the possible folds ( where fold is a single stable form - obviously there are quite a lot of disordered states - but I'm not including those in a 'fold' even if evolution uses unstructured states as well) already.

Re: The Unreasonable Redundancy of Nature's Protein Folds

#54

Post by jyounker »

HarHarVeryFunny wrote: post #34
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…

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) ?

> What do you mean by "reaction center"

An enzymatic reaction center is also known as an "active size". It's the location within an enzyme's 3D structure where catalysis happens.

Re: The Unreasonable Redundancy of Nature's Protein Folds

#55

Post by jyounker »

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…

I have a 30 year old book on protein structure on my shelf. One of the primary themes is the recurrence of the same structural motifs in proteins. The fact that biologic proteins use the same patterns for different functions isn't new information.

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.

Re: The Unreasonable Redundancy of Nature's Protein Folds

#56

Post by jyounker »

HarHarVeryFunny wrote: post #34
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…

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) ?

> So what are the lessons here?

The only lesson is that, to a biochemist, the result is not surprising.

Re: The Unreasonable Redundancy of Nature's Protein Folds

#57

Post by nickpsecurity »

dekhn wrote: post #48

I worked with a foodie who was also a protein scientist ( 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.

How so?

Re: The Unreasonable Redundancy of Nature's Protein Folds

#58

Post by jeejay1 »

gilleain wrote: post #8
jeejay1 wrote: post #5

Earlier quoted context omitted.

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

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.

Do you have an example of such sequences in mind? Because I can’t recall any example.

Re: The Unreasonable Redundancy of Nature's Protein Folds

#59

Post by DrScientist »

jyounker wrote: post #55
DrScientist wrote: post #41

Earlier quoted context omitted.

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…

I have a 30 year old book on protein structure on my shelf. One of the primary themes is the recurrence of the same structural motifs in proteins. The fact that biologic proteins use the same patterns for different functions isn't new information. 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, the…

> I have a 30 year old book on protein structure on my shelf. One of the primary themes is the recurrence of the same structural motifs in proteins.

What you have to be careful about here is that the structure that were available 30 years ago were quite strongly biased by what was experimentally tractable.... ie the recurrence of the same folds is in part related to what crystallised well.

> The fact that biologic proteins use the same patterns for different functions isn't new information.

Absolutely. The question is how big is the space - and what percentage of it have we already seen.

> The variety of classes of chemicals that can exist dwarfs what gets used in biochemistry. Why would we expect structure to be different?

Depends on whether the structure universe is specifically a small almost fully explored subset for that very reason. ie biology has choosen a structural subset of possible chemical space by choosing a tiny subset of chemistry.

Re: The Unreasonable Redundancy of Nature's Protein Folds

#60

Post by jyounker »

DrScientist wrote: post #59
jyounker wrote: post #55

Earlier quoted context omitted.

I have a 30 year old book on protein structure on my shelf. One of the primary themes is the recurrence of the same structural motifs in proteins. The fact that biologic proteins use the same patterns for different functions isn't new information. 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, the…

> I have a 30 year old book on protein structure on my shelf. One of the primary themes is the recurrence of the same structural motifs in proteins. What you have to be careful about here is that the structure that were available 30 years ago were quite strongly biased by what was experimentally tractable.... ie the recurrence of the same folds is in part related to what crystallised well. > The fact that biologic pr…

> What you have to be careful about here is that the structure that were available 30 years ago were quite strongly biased by what was experimentally tractable.... ie the recurrence of the same folds is in part related to what crystallised well.

It was biased in some sense towards those things that could be crystalized, but but at that time we were already seeing the same sorts of recurring motifs with cryo-em which is much less restrictive in the required preparations. (Purify it and flash freeze it.)

In the last 30 years there's nothing that has overturned the recurrence of motifs in protein structure. It's just become more and more established.

This paper confirms that.

The methods they're using are interesting, but the fundamental result isn't surprising.

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