Live data from Hacker News

AI Revolutionized Protein Science, but Didn't End It

quantamagazine.org

11–20 of 39 posts

Re: AI Revolutionized Protein Science, but Didn't End It

#11
post #8
post #4

Earlier quoted context omitted.

> Protein folding is still an unsolved problem, and I’m dubious of the notion machine learning will ever solve it, but hopefully we get some helpful science out of it. As a working hypothesis, protein folding assumes that a protein folds into the globally lowest energy configuration. And that's a good assumption for a start. However, nature isn't magic and can't magically solve global optimisation problems. If there'…

> Why are you dubious? Where do your objections come from? That the results the machine learning techniques provide are still nondeterministic. Meaning that they are, in terms of identifying other local minima that satisfy the constraints, as good as a guess. If the provided solution also came with a method of systemic modification to derive all other solutions that satisfy the constraints, then I would be satisfied.…

> That the results the machine learning techniques provide are still nondeterministic.

I think I know what you are trying to say, but 'determinism' or not isn't the problem. You can run machine learning methods completely deterministically: just use a pseudo-random-number-generator (and be careful about how you seed it, and be wary of the problems with concurrency etc).

> If the provided solution also came with a method of systemic modification to derive all other solutions that satisfy the constraints, then I would be satisfied.

> Without that you are unable to say with certainty that your local minima is correct even if nature fails to adhere to the lowest energy assumption.

Have a look at how integer linear programming solvers work. They use plenty of heuristics and non-determinism for finding the solution, but at the end they can give you a proof that what they found is optimal.

You are right, that you don't get that kind of guarantee with current machine learning approaches. Though you could modify them in that direction. (Eg if you added machine learning to an integer linear programming solver, you would hook it in as a new heuristic, but you would still want the proof at the end.)

> I have a long standing hypothesis that an algorithmic solution to the global optimization problem is what lends action potentials the appearance, or essence?, of what we mean when we speak of “consciousness”.

Sounds like woo. Protein folding in bacteria and yeast work pretty similar to how it works in humans. In fact, we can transfer genes from us to yeasts to produce many of the same proteins human produce. But you'd be hard-pressed to argue that yeast are sentient.

This reminds me of how some people claim that soap films are super special because those films can solve optimisation problems. See eg https://highscalability.com/why-my-soap-film-is-better-than-... If you put soap film between a bunch of supports, even if the supports have complicated shapes, the soap film will tend to minimise its overall surface area.

Of course, if you look deeper into it, and do larger scale experiments, you figure out that the soap only assumes a local minimum.

Re: AI Revolutionized Protein Science, but Didn't End It

#12
post #9
post #6

Earlier quoted context omitted.

I'm a mathematician but tbh I have no clue what you mean by saying that arithmetic progressions of primes are "trivial" or analogous to anything here or in machine learning.

Yeah, the messaging got a little muddled, but the relation was purely analogical. I was trying to point to a situation where you have a clear problem: a generating function for the prime number sequence; and a solution that identifies a small subset of the intended sequence without addressing, or even informing in any substantial way, the full breadth of the original problem. > At the time of writing the longest know…

It would be very hard to make a good analogy with this since the problem of "finding" arithmetic progressions is, as far as I know, of negligible interest compared to the structural knowledge of their existence. The situation is perfectly reversed in both computational biology and machine learning. But maybe I misunderstand what you mean by "a complete solution to the prime number sequence."

Re: AI Revolutionized Protein Science, but Didn't End It

#13
post #5

Great article, covers well both the achievements and the shortcomings. It's crazy how many people write about these kinds of AI developments while completely skipping over anything like the following: > The “good news is that when AlphaFold thinks that it’s right, it often is very right,” Adams said. “When it thinks it’s not right, it generally isn’t.” However, in about 10% of the instances in which AlphaFold2 was “v…

Tale as old as ML: people don’t understand it’s an assistance tool, and instead assume it’s always right. Crazy how we tend to wave away even errors rates of 1% or less. One in a thousand is a lot.

It really depends on the context; (Some) LLMs look impressive specifically because the error rate is comparable to a high score on an exam… the mistake is that even if it was a straight-A student (it's too alien to be that) then it would still only be a student, and we don't put fresh graduates in charge of everything important.

I don't have the domain knowledge to even guess how good 90% is in molecular biology research.

Re: AI Revolutionized Protein Science, but Didn't End It

#14
"...Some cell biologists and biochemists who used to work with structural biologists have replaced them with AlphaFold2 — and take its predictions as truth. Sometimes scientists publish papers featuring protein structures that, to any structural biologist, are obviously incorrect, Perrakis said. “And they say: ‘Well, that’s the AlphaFold structure.’”"

It is amazing that this happens. I am not naive about academic standards, but if something is clearly wrong and used in a paper (especially one with consequences on medical health) then it should be quite easy to name-and-shame until the editors of the journal force the authors to make a redaction or correction if the authors don't do it themselves. Otherwise people should start name-and-shame the journal and its reputation should sink.

Also I am curious if there are already lists of known incorrect predictions by Alphafold, shouldn't this be published and alphafold's database tag such predictions accordingly to notify users that these particular predictions are proven to be wrong.

Re: AI Revolutionized Protein Science, but Didn't End It

#15
post #4
post #3

Weird article. It mentions multiple times that ~”the protein folding problem is solved” as well as multiple instances of ~”but there are limitations to this technique and it is often missing crucial details”. It really is difficult to conceptualize these highly nonlinear problem spaces, like protein folding, until you attempt to work with them. Many in software development have an intuitive understanding of the diffi…

> Protein folding is still an unsolved problem, and I’m dubious of the notion machine learning will ever solve it, but hopefully we get some helpful science out of it. As a working hypothesis, protein folding assumes that a protein folds into the globally lowest energy configuration. And that's a good assumption for a start. However, nature isn't magic and can't magically solve global optimisation problems. If there'…

> As a working hypothesis, protein folding assumes that a protein folds into the globally lowest energy configuration. [...] If there's a region in configuration space with a local minimum and high enough energy 'walls', this might be stable enough for the protein to be stable.

Sounds like gradient descent :)

Re: AI Revolutionized Protein Science, but Didn't End It

#16
post #4
post #3

Weird article. It mentions multiple times that ~”the protein folding problem is solved” as well as multiple instances of ~”but there are limitations to this technique and it is often missing crucial details”. It really is difficult to conceptualize these highly nonlinear problem spaces, like protein folding, until you attempt to work with them. Many in software development have an intuitive understanding of the diffi…

> Protein folding is still an unsolved problem, and I’m dubious of the notion machine learning will ever solve it, but hopefully we get some helpful science out of it. As a working hypothesis, protein folding assumes that a protein folds into the globally lowest energy configuration. And that's a good assumption for a start. However, nature isn't magic and can't magically solve global optimisation problems. If there'…

Great points about the energy minimisation issue. Funnily enough, this is actually a problem with de-novo protein design at the moment: the designed proteins are _too_ stable! Compared to natural proteins. Protein are often not static shapes, they are machines that need to be dynamic - in other words what you said, they do not live at some deep global optimum.

Re: AI Revolutionized Protein Science, but Didn't End It

#17
post #16
post #4

Earlier quoted context omitted.

> Protein folding is still an unsolved problem, and I’m dubious of the notion machine learning will ever solve it, but hopefully we get some helpful science out of it. As a working hypothesis, protein folding assumes that a protein folds into the globally lowest energy configuration. And that's a good assumption for a start. However, nature isn't magic and can't magically solve global optimisation problems. If there'…

Great points about the energy minimisation issue. Funnily enough, this is actually a problem with de-novo protein design at the moment: the designed proteins are _too_ stable! Compared to natural proteins. Protein are often not static shapes, they are machines that need to be dynamic - in other words what you said, they do not live at some deep global optimum.

Interesting point!

> [...] in other words what you said, they do not live at some deep global optimum.

I think what you said only depends on the minimum being relatively flat (instead of deep); but it doesn't matter whether it's global or local.

Re: AI Revolutionized Protein Science, but Didn't End It

#18
post #15
post #4

Earlier quoted context omitted.

> Protein folding is still an unsolved problem, and I’m dubious of the notion machine learning will ever solve it, but hopefully we get some helpful science out of it. As a working hypothesis, protein folding assumes that a protein folds into the globally lowest energy configuration. And that's a good assumption for a start. However, nature isn't magic and can't magically solve global optimisation problems. If there'…

> As a working hypothesis, protein folding assumes that a protein folds into the globally lowest energy configuration. [...] If there's a region in configuration space with a local minimum and high enough energy 'walls', this might be stable enough for the protein to be stable. Sounds like gradient descent :)

Well, or hill climbing in general.

Re: AI Revolutionized Protein Science, but Didn't End It

#19
post #5

Great article, covers well both the achievements and the shortcomings. It's crazy how many people write about these kinds of AI developments while completely skipping over anything like the following: > The “good news is that when AlphaFold thinks that it’s right, it often is very right,” Adams said. “When it thinks it’s not right, it generally isn’t.” However, in about 10% of the instances in which AlphaFold2 was “v…

Tale as old as ML: people don’t understand it’s an assistance tool, and instead assume it’s always right. Crazy how we tend to wave away even errors rates of 1% or less. One in a thousand is a lot.

This tool is designed to be helpful right now. Looking ahead, there's no reason why AI can't eventually match, or even surpass, human intelligence across the board.

Whether it's advancements in LLMs, with features like long-term memory, or breakthroughs in other areas of ml, it's not guaranteed that humans will remain needed in the research process.

Re: AI Revolutionized Protein Science, but Didn't End It

#20
post #5

Great article, covers well both the achievements and the shortcomings. It's crazy how many people write about these kinds of AI developments while completely skipping over anything like the following: > The “good news is that when AlphaFold thinks that it’s right, it often is very right,” Adams said. “When it thinks it’s not right, it generally isn’t.” However, in about 10% of the instances in which AlphaFold2 was “v…

> However, in about 10% of the instances in which AlphaFold2 was “very confident” about its prediction (a score of at least 90 out of 100 on the confidence scale)

I wonder what that confidence score means... If it is 90% probability, then we'd expect it to be wrong 10% of the time

Post reply on HN