Chemistry Nobel: Computational protein design and protein structure prediction

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 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 bunch of ad-hoc hand-coded features and optimizers). he chuckled and said he doubted it, every time he updated the Rosetta model with newer PDB structures, the predictions got worse.

I will say that the Nobel committee needs to stop saying "protein folding" when they mean "protein structure prediction".

Demis Hasabis has a really interesting and unusual CV for a nobel laureate [1], he started his career in AI game programming (he worked e.g. on Popoulous II, Syndicate, Theme Park for Bullfrog, and later for Lionhead Studios on Black & White) before doing a PhD in neuroscience, becoming an entrepreneur and starting DeepMind. I would say this is a refreshing and highly uncommon pick for a nobel prize, really cool to see that you don't have to be a university professor anymore to do this kind of impactful research.

1: https://en.wikipedia.org/wiki/Demis_Hassabis

While I am skeptical about yesterdays award in physics, these are totally deserved and spot on. There are few approaches that will accelerate the field of drug development and chemistry as a whole in a way that the works of these three people will. Congratulations!

I think putting AlphaFold here was premature; it might not age well. AlphaFold is an impressive achievement but it simply has not "cracked the code for protein folding" - about 1/3rd of its predictions are too uncertain to be usable, it says nothing about dynamics, suffers from the same ML problems of failing on uncommon structures, and I was surprised to learn that many of its predictions are incorrect because it ignores topological constraints[1]. To be clear, these are constructive criticisms of AlphaFold in isolation, my grumpiness is directed at the Nobel committee. "Cracked the code for protein folding" is simply not true; it is an ML approach with high accuracy that suffers the same ML limitations of failing to generalize or failing to understand deeper principles like R^3 topology that cannot be gleaned stochastically.

More significantly: it has yet to be especially impactful in biochemistry research, nor has its results really been carefully audited. Maybe it will turn out to deserve the prize. But the committee needed to wait. I am concerned that they got spun by Google's PR campaign - or, considering yesterday's prize, Big Tech PR in general.

[1] https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10672856/

Physics prize one goes to AI, chemistry too. What next? Nobel in Literature goes to ChatGPT?

Jokes aside, I think the chemistry prize seems to make a bit more sense to me than physics one.

AlphaFold is a useful tool but it's unsatisfying from a physical chemistry perspective. It doesn't give much if any insight in to the mechanisms of folding, and is of very limited value in designing novel proteins with industrial applications, and in protein prediction for membrane-spanning proteins, extremophilic microbe proteins, etc.

Thus things like folding kinetics of transition states and intermediates, remain poorly understood through such statistical models, because they do not explicitly incorporate physical laws governing the protein system, such as electrostatic interactions, solvation effects, or entropy-driven conformational changes.

In particular, environmental effects are neglected - there's no modeling of the native solvated environment, where water molecules, ions, and temperature directly affect the protein’s conformational stability. This is critical when it comes to designing a novel protein with catalytic activity that's stable under conditions like high salt, high temperature etc.

As far as Nobel Prizes, it was already understood in the field two decades ago that no single person or small group was going to have an Einstein moment and 'solve protein folding', it's just too complicated. This award is questionable and the marketing effort involved by the relevant actors has been rather misleading - for one of the worst examples of this see:

https://www.scientificamerican.com/article/one-of-the-bigges...

For a more judicious explanation of why the claim that protein folding has been solved isn't really true:

"The power and pitfalls of AlphaFold2 for structure prediction beyond rigid globular proteins" (June 2024)

https://www.nature.com/articles/s41589-024-01638-w

Looks like science is out, black box prediction is in. It's like the era of epicycles all over again.

Oh well. Fellow realists, see you all 1500 years from now!

Yesterday's physics win was rather odd but this I have no problem with!

Lol does this mean there's a chance the Transformer Authors win a Nobel in literature sometime? Certainly seems a lot more plausible than before yesterday.

I think it's still too early to know if AlphaFold is a massively overfitted statistical model that will utterly fail on novel structures.

Combine this with the Physics prize, I now have hope to receive a Nobel prize in any area. Seriously, from now on, I won't mention Nobel prizes anywhere anymore.

David Baker (and colleagues) have always done good work. I guess google have done some things also.

(lol - one of the PDF attachments to that page is 'Illustration: A string of amino acids' : actually it's a bit better than the title implies :).

Actually, Figure 2 - "How does AlfaFold2 Work?" is impressive to fit that on one page. Nice.

For those like myself who design proteins for a living, the open secret is that well before AlphaFold, it was pretty much possible to get a good-enough structure of any particular protein you really cared about (from say 2005) by other means, namely Baker’s Rosetta.

I constantly use AlphaFold structures today [1]. And AlphaFold is fantastic. But it only replaces one small step in solving any real-world problem involving proteins such as designing a safe, therapeutic protein binder to interrupt cancer-associated protein-protein interactions or designing an enzyme to degrade PFAS.

I think the primary achievement is that it gets protein structures in front of a lot more smart eyes, and for a lot more proteins. For “everyone else” who never needed to master computational protein structure prediction workflows before, they now have easy access to the rich, function-determinative structural information they need to understand and solve their problem.

The real tough problem in protein design is how to use these structure predictions to understand and ultimately create proteins we care about.

1. https://alexcarlin.bearblog.dev/multistate-protein-design-wi...

So between this and the award for physics, it's basically a clean sweep of the Nobel prizes this year for AI. Quite a moment if you stand back and think about that.

To me this is more controversial than Geoffrey Hinton winning it for physics.

Did Demis Hasabis actually do any scientific work himself?

Well deserved! Especially for Alphafold. It is the most impactful invention in structural biology this century along with Cryo-EM.

I see a number of comments here about giving awards to organizations rather than individuals, and counter-comments pointing out that Nobel's will disallowed it.

How is the Nobel Prize actually administered? For how long is the Nobel committee bound to follow Alfred Nobel's will? And aren't there laws against perpetual trusts? Or is the rule against awarding the technical awards to organizations one that the committee maintains out of deference to Nobel's original intentions?

As a computer scientist who is oppositional to AGI boom-bubble mania, it was easy to decry the Nobel in physics. But, contextually given who Murray Gell-Mann was and what field he was in (astrophysics) I feel a very strong Gell-Mann Effect here because I am happy to accept THIS use of computational systems to advance (bio)chemistry is worthy, and I find myself wondering why I am so uncritical about it?

Anyone else think that giving a nobel prize to the CEO of the company is absurd?

For some reason this web page doesn't render properly in my browser. The main text overlaps the table of contents.

I'm using Chrome on KDE (Ubuntu) on a 1920 wide display (minus the side panel). I checked and I don't have the page zoomed.

https://i.imgur.com/fOOQ3Av.png

AI is cleaning up at the nobel prizes!

... and the Nobel in Economics goes to OpenAI for innovations in nonprofit business structures.

it's the year of AI (ChatGPT preparing its acceptance speech)

Huh, so both the chemistry Nobel and the physics Nobel were for neural networks this year. That's astounding.

Calling it, to keep with the theme: the Nobel prize in literature will be given to a LLM author.

Feeling a bit down today, so just asking: when can we realistically expect to see the (positive) effects of this Nobel in daily life, and what would they be ? (I understand it's helping biotech a lot, but helping them do... what exactly ?)

I'm not always a Lex Fridman fan, but the interview with Demis is well worth a listen.

Well more deserving than the author of Restricted Boltzmann machine.

And, at the heart of AlphaFold2 is the language model, the tip of the spear in AI today. 'Language' can come in many forms e.g. a protein or amino acid sequence.

Its the AI Nobels. First physics and now chemistry. Demis Hasabis getting the prize for Chemistry is not something I would have ever expected though.

Nobel peace prize has countless times been awarded to a group of people or institution. It is differently controlled but the idea is not unprecedented.

Nobel committee is all in on the AI hype this year!

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.

excellent longread on the development of AlphaFold - with interviews with Baker + Jumper and more: https://www.quantamagazine.org/how-ai-revolutionized-protein...

First physics and now chemistry. I wonder if we’ll see AI/ML-powered work in most prizes going forward.

How come they missed Justin Gilmer? He did most of the original work [0].

[0] https://scholar.google.com/citations?view_op=view_citation&h...

EDIT: typos

Prediction: Demis Hasabis will win second Nobel.

Congrats to David Baker and his lab!

Nice one Demis & Chums!

Now this one makes more sense. Chemistry Nobel for advancing chemistry using AI.

Contrast that with Phyics Nobel for advancing AI using physics.

inb4 Nobel Peace Prize will go to Timnit Gebru

people still folding@home <shrug>

Whoa. Happy for Demis today. Amazing achievement.

well deserved

The AlphaFold paper has countless authors, many researchers and company resources underlying it. Hassabis’ contribution is management of resources and entrepreneurship, not the actual science. There are hundreds of thousands of scientists out there doing deep technical work, and they aren’t recognized.

I think we might be the end of it, as the emphasis shifts to commercialization and product development.

These AI demonstrations require so many GPUs, specialized hardware and data that nobody has but the biggest players. Moreover, they are engineering work, not really scientistic (putting together a lot of hacks and tweaks). Meanwhile, the person who led the transformer paper (a key ingredient in LLMs) hasn’t been recognized.

This will incentivize scientists to focus on management of other researchers who will manage other researchers who will produce the technical inventions. The same issue arises with citations and indices, and the general reward structure in academia.

The signal these AI events convey to me: You better focus on practical stuff, and you better move on in the management ladder.

Here's a direct quote from the Alphafold paper:

"These authors contributed equally: John Jumper, Richard Evans, Alexander Pritzel, Tim Green, Michael Figurnov, Olaf Ronneberger, Kathryn Tunyasuvunakool, Russ Bates, Augustin Žídek, Anna Potapenko, Alex Bridgland, Clemens Meyer, Simon A. A. Kohl, Andrew J. Ballard, Andrew Cowie, Bernardino Romera-Paredes, Stanislav Nikolov, Rishub Jain, Demis Hassabis"

Great achievement, although I think it's interesting that this Nobel prize was awarded so early, with "the greatest benefit on mankind" still outstanding. Are there already any clinically approved drugs based on AI out there I might have missed?

In comparison, the one for lithium batteries was awarded in 2019, over 30 years after the original research, when probably more than half of the world's population already used them on a daily basis.

People joked maybe the Nobel committee is holding some AI stocks. Now I start to wonder if that is true...

> Oppenheimer was nominated for the Nobel Prize for Physics three times[...] pondered why he was never bestowed the honor.

> “To understand this [...] you have to first examine the man’s academic life before and after the war.”

Quote from: https://discover.lanl.gov/news/0609-oppie-nobel-prize/

Not anymore. You're not required to know or have studied Chemistry to get a Nobel in Chemistry.

First Obama got the Peace Prize Nobel, now Demis Hassabis gets the Chemistry Nobel. I expect at a minimum the Nobel Prize in Literature to be Donald E. Knuth.

And the literature Nobel will go for ChatGPT

Nobel prize committee really sending some messages this year on what constitutes benefiting humanity the most.

The physics prize was a stretch of the definition of the word "physics", but this one is purely about chemistry.

I wonder why various outlets, including DeepMind's blog, say that John Jumper is a "Senior Research Scientist". That's L5 which sounds like quite a low rank for a Nobel prize winner. I checked his LinkedIn and he's a director, which is around L8. I thought that maybe he was L5 during the publishing of the results, but no, he was either L6 or L7.