Chemistry Nobel: Computational protein design and protein structure prediction • Hacker News Board

Re: Chemistry Nobel: Computational protein design and protein structure prediction

#221

Post by nextos » Wed, Oct 09, 2024, 4:38 PM UTC

mhrmsn wrote: post #180

eig wrote: post #117

I think I disagree with most of the comments here stating it’s premature to give the Nobel to AlphaFold. I’m in biotech academia and it has changed things already. Yes the protein folding problem isn’t “solved” but no problem in biology ever is. Comparing to previous bio/chem Nobel winners like Crispr, touch receptors, quantum dots, click chemistry, I do think AlphaFold already has reached sufficient level of impact.

Crispr is widely used and there are even therapies approved based on it, you can actually buy TVs that use quantum dots and click chemistry has lots of applications (bioconjugation etc.), but I don't think we have seen that impact from AlphaFold yet. There's a lot of pharma companies and drug design startups that are actively trying to apply these methods, but I think the jury is still out for the impact it will fina…

AlphaFold is excellent engineering, but I struggle calling this a breakthrough in science. Take T cell receptor (TCR) proteins, which are produced pseudo-randomly by somatic recombination, yielding an enormous diversity. AlphaFold's predictions for those are not useful. A breakthrough in folding would have produced rules that are universal. What was produced instead is a really good regressor in the space of proteins where some known training examples are closeby.

If I was the Nobel Committee, I would have waited a bit to see if this issue aged well. Also, in terms of giving credit, I think those who invented pairwise and multiple alignment dynamic programming algorithms deserved some recognition. AlphaFold built on top of those. They are the cornerstone of the entire field of biological sequence analysis. Interestingly, ESM was trained on raw sequences, not on multiple alignments. And while it performed worse, it generalizes better to unseen proteins like TCRs.

Re: Chemistry Nobel: Computational protein design and protein structure prediction

#222

Post by flobosg » Wed, Oct 09, 2024, 4:43 PM UTC

nextos wrote: post #221

mhrmsn wrote: post #180

Earlier quoted context omitted.

Crispr is widely used and there are even therapies approved based on it, you can actually buy TVs that use quantum dots and click chemistry has lots of applications (bioconjugation etc.), but I don't think we have seen that impact from AlphaFold yet. There's a lot of pharma companies and drug design startups that are actively trying to apply these methods, but I think the jury is still out for the impact it will fina…

AlphaFold is excellent engineering, but I struggle calling this a breakthrough in science. Take T cell receptor (TCR) proteins, which are produced pseudo-randomly by somatic recombination, yielding an enormous diversity. AlphaFold's predictions for those are not useful. A breakthrough in folding would have produced rules that are universal. What was produced instead is a really good regressor in the space of proteins…

> A breakthrough in folding would have produced folding rules that are universal.

Protein folding ≠ protein structure prediction

> I think those who invented pairwise and multiple alignment dynamic programming algorithms deserved some recognition

I would add BLAST as well but that ship has sailed, I’m afraid.

Re: Chemistry Nobel: Computational protein design and protein structure prediction

#223

Post by [deleted] » Wed, Oct 09, 2024, 4:50 PM UTC

dekhn wrote: post #153

I wasn't expecting to see David Baker in the list (just Demis and John). But I'm really glad to see it... David is a great guy. At CASP (the biannual protein structure prediction competition) around 2000, I sat down with David and told him that eventually machine learning would supplant humans at structure prediction (at the time Rosetta was already the leading structure prediction/design tool, but was filled with a…

[deleted]

Re: Chemistry Nobel: Computational protein design and protein structure prediction

#224

Post by flobosg » Wed, Oct 09, 2024, 4:54 PM UTC

causal wrote: post #216

eig wrote: post #117

I think I disagree with most of the comments here stating it’s premature to give the Nobel to AlphaFold. I’m in biotech academia and it has changed things already. Yes the protein folding problem isn’t “solved” but no problem in biology ever is. Comparing to previous bio/chem Nobel winners like Crispr, touch receptors, quantum dots, click chemistry, I do think AlphaFold already has reached sufficient level of impact.

I agree. For those not in biotech, protein folding has been the holy grail for a long time, and AlphaFold represents a huge leap forward. Not unlike trying to find a way to reduce NP to P in CS. A leap forward there would be huge, even if it came short of a complete solution.

> Let me get the most important question out of the way: is AlphaFold’s advance really significant, or is it more of the same? I would characterize their advance as roughly two CASPs in one

―https://moalquraishi.wordpress.com/2018/12/09/alphafold-casp...

Re: Chemistry Nobel: Computational protein design and protein structure prediction

#225

Post by huijzer » Wed, Oct 09, 2024, 4:55 PM UTC

BeetleB wrote: post #176

seydor wrote: post #70

Earlier quoted context omitted.

doesn't beat that patent clerk guy

The patent clerk guy was almost done with his PhD when he became a patent clerk. Not quite comparable.

Are we talking about Einstein? If I remember correctly, according to Walter Isaacson, Einstein managed to get so many good papers out not despite, but because he was not working for an university. It gave him more freedom to reject existing ideas. Also the years I can find on Wikipedia do not seem to support your claim. He started as a clerk in 1903, and had his miracle year and submitted his PhD dissertation in 1905.

Re: Chemistry Nobel: Computational protein design and protein structure prediction

#226

Post by huijzer » Wed, Oct 09, 2024, 4:58 PM UTC

PaulDavisThe1st wrote: post #170

DevX101 wrote: post #155

Earlier quoted context omitted.

If you gave the $300,000 Bezos got from his father to 10,000 random Americans in 1994, none of them would have created a company the equivalent of Amazon's scale.

10k random Americans, sure. 10k random Americans with backgrounds in software and a business idea? Not so clear. You also seem very certain that Amazon's scale is a good thing, overall, which I remain unconvinced of.

> You also seem very certain that Amazon's scale is a good thing, overall, which I remain unconvinced of.

What do you find unconvincing about roughly 30 billion in net income and free cashflow in 2023?

Re: Chemistry Nobel: Computational protein design and protein structure prediction

#227

Post by itishappy » Wed, Oct 09, 2024, 4:58 PM UTC

varelse wrote: post #181

stonemetal12 wrote: post #169

Earlier quoted context omitted.

How many of those 10k would have the same background? We can pretend Bezos' dad raised him in a "normal" middle class background then randomly dropped 300K on him, or we can acknowledge he is the business equivalent of an Olympic athlete.

Bezos? Abandoned by his dad who was literally an alcoholic clown and raised by his mom and her 2nd husband Bezos? https://en.wikipedia.org/wiki/Ted_Jorgensen So $300K in 1994 is about $640K. That's nice but about 80th percentile of net worth. It's nice his parents believed in him. How many of your parents would do that for you? I'm sure at 1 in 5 of them have that kind of money because of the distribution here. So th…

I assumed the parent post was talking about his adopted father. The man who raised and dropped $250k on Bezos was Miguel.

https://en.wikipedia.org/wiki/Miguel_Bezos

Re: Chemistry Nobel: Computational protein design and protein structure prediction

#228

Post by muenalan » Wed, Oct 09, 2024, 5:01 PM UTC

Surely, it is helpful to consider the achievement in terms of the contest setup to detect a Nobel-worthy breakthrough: https://en.m.wikipedia.org/wiki/CASP

It moved the needle so much in terms of baseline capability. Let alone Nobel’s original request: positive impact to humanity; well deserved.

In biology/medicine it is still awed like coming from a different planet; tech before was obviously that lacking.

Re: Chemistry Nobel: Computational protein design and protein structure prediction

#229

Post by dekhn » Wed, Oct 09, 2024, 5:05 PM UTC

timr wrote: post #217

dekhn wrote: post #195

Earlier quoted context omitted.

It solidly answered the question: "Is evolutionary sequence relationship and structure data sufficient to predict a large fraction of the structures that proteins adopt". the answer, surprising few, is that the data we have indeed can be used to make general predictions (even outside of the training classes), and also surprising many, that we can do so with a minimum of evolutionary sequence data. That people are arg…

That's a bit like saying that the invention of the airplane proved that animals can fly, when birds are swooping around your head. I mean, sure, prior to alphafold, the notion that sequence / structure relationship was "sufficient to predict" protein structure was merely a very confident theory that was used to regularly make the most reliable kind of structure predictions via homology modeling (it was also core to R…

I think an important detail here is that Rosetta did something beyond traditional homology models- it basically shrank the size of the alignments to small (n=7 or so?) sequences and used just tiny fragments from the PDB, assembled together with other fragments. That's sort of fundamentally distinct from homology modelling which tends to focus on much larger sequences.

Re: Chemistry Nobel: Computational protein design and protein structure prediction

#230

Post by divbzero » Wed, Oct 09, 2024, 5:07 PM UTC

eig wrote: post #117

I think I disagree with most of the comments here stating it’s premature to give the Nobel to AlphaFold. I’m in biotech academia and it has changed things already. Yes the protein folding problem isn’t “solved” but no problem in biology ever is. Comparing to previous bio/chem Nobel winners like Crispr, touch receptors, quantum dots, click chemistry, I do think AlphaFold already has reached sufficient level of impact.

I agree that it’s not premature, for two reasons: First, it’s been 6 years since AlphaFold first won CASP in 2018. This is not far from the 8 years it took from CRISPR’s first paper in 2012 to its Nobel Prize in 2020. Second, AlphaFold is only half the prize. The other half is awarded for David Baker’s work since the 1990s on Rosetta and RoseTTAFold.