Comment by DrScientist | Hacker News Reader

Comment by DrScientist | Hacker News Reader

As the summary says, the basic approach ( evolutionary data -> position coupling -> to distance restraints - into structure solver ) is actually quite old, with the key paper back in 2011.

In fact, the distance constraints to 3D structure part is in fact very old - I was calculating structures from experimentally determined distances 30 years ago. You need a surprisingly low number of fairly weak ( these atoms are between 3 and 5 Angstroms ) distances to determine a 3D structure if you have a decent number of long range ones.

What they have done is execute better.

However the problem they are working on

sequence -> structure

though it's been a long term 'holy grail', practically it's not that useful!

The models typically aren't quite good enough, it's not predicting interactions, and experimental methods to determine structures have also moved on in leaps and bounds.

As the article briefly mentions what you really want to do is go the other way.

Designed novel structure -> protein sequence to make it.

One way to do that if you have a function going the other way ( like alphafold ( let's ignore limitations for now - ie does a knowledge based approach work well for completely novel folds ? ) ), is some sort of heuristic search - however the search space is huge and a step size of hours isn't going to cut it.

> However the problem they are working on

> sequence -> structure

I recall reading about a result a couple of years ago supposedly demonstrating that "synonymous" DNA codons were in fact not synonymous, because the ribosome took systematically different amounts of time to process them, and the difference in construction time resulted in different folding for the protein.

This would imply that the problem "sequence -> structure" is not well defined, at least if the sequence in question is the sequence of peptides making up the protein and not the sequence of codons making up the gene that codes for the protein.

Do you know anything about this? Am I just making it up?

I think it's much more likely that the different codon usage leads to different rates of synthesis, not differently folded proteins. But that's a complex area. Many proteins do not fold to their native structure spontaneously, and there are other proteins that refold them "correctly".

It's not clear to me that you could truly demonstrate substantially different folding due to codon usage like that, on an experimental level, to make a general statement about all proteins.

> Many proteins do not fold to their native structure spontaneously, and there are other proteins that refold them "correctly".

This would also seem to imply that "sequence -> structure" isn't quite the right problem.

well, not sure what you mean by "Sequence->structure". Historically, people have used the fact that small globular proteins refold spontaneously and rapidly to their native state to support the idea that there is a single, unique structure encoded by a specific sequence. That's a helpful if ultimately limited approach (as we observe many proteins that don't fold rapidly to single native structure).

That's a reason that evolution-based methods, which use statistics about families of related proteins to estimate distances between pairs of amino acids (in 3D space), are more effective- many times in biology we can use evolutionary relationships between proteins to infer things that would be hard to determine through experiments or rigorous, thorough simulations.

But it's important to appreciate there are a large number of proteins that don't fold to a single unique structure rapidly-- and there are many ways this can be the case and many different biologically relevant behaviors depend on these properties. The tools from CASP are much less useful for proteins that violate the assumptions of Anfinsen's dogma, although the evolutionary data is helpful there too, it can often be a lot more challenging to deconvolute the signal.

Ultimately, "what is the right problem"? THe one that makes the most money? Produces the most "useful" scientific result? Is accessible with today's technology? For now, there's plenty of value in these sorts of competitions.

Personally I think the "right problem" is: "given a collection of diseases, use experimentally derived data and clever math, to discover biological treatments that reduce the total suffering from those diseases, subject to monetary and ethical constraints". That's what pharma attempts to do, although not particularly well. Others might say simply solving interesting problems like protein folding is inherently valuable as the right problem.

It's true, that different codons are transcribed with different speed but I've never heard that this would lead to differences in folding. Speed of translation is nevertheless used in order to signal shortage of amino acids or to implement modification.

When you're doing protein expression, it's a standard procedure to do a codon optimization in order to adapt the codons to your host expression system. When you're expressing a human protein in yeast or ecoli the codons will be quite different but the folding is the same. If translation wouldn't show this stability it would be difficult to use foreign expression systems at all.

The phenomenon you described does exist[0], and similar effects (though rarely as severe) in cotranslational folding have been known for some time now. AFAIK it's not studied that intensely, as it's hard to study experimentally, and it is not expected to have a significant effect on final protein folding. During the folding process proteins often undergo partial misfolds, and defold again (the protein is basically doing a gradient descent search for the lowest energy state), so a small misfold at the beginning of the the translation process will rarely make it into the final fold.

Apart from protein folding there are other interfering folding mechanisms like chaperone proteins that also make it hard to phrase it as a straight "sequence -> structure" prediction problem, though they often only exist for a small number of the total proteins (in humans).

[0]: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5737824/

It's biology - so there are exceptions and oddities everywhere.

Imagine software that evolved by trial and error rather than being designed - it's not 'clean'... there are no absolutes.

It's well known that codons effect translation rate and translation rate could/can effect the kinetic pathway of folding.

When a protein folds ( even away from the ribosome ) it isn't in isolation - it's in a solution - being bombarded by Brownian motion of other molecules.

It's amazing you are alive at all really - it also suggests most proteins would need the functional state to be strongly energetically preferred.

So there are potentially lots of things beyond just the protein sequence that could be important variables.

However some proteins will reversibly fold/unfold in simple solution all day long - so it makes sense to start there.

Is the bit by bit construction of the protein an issue? I mean, surely the first half would have already folded into some shape by the time the second half was be added on? And then the rest of it would not necessarily fold the same way as if you considered the entire completed protein starting to fold from scratch.

> however the search space is huge and a step size of hours isn't going to cut it.

What's the rush?

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