4 ms·

The point is that given a solution to protein folding, we can then compare that solution with current theory and even physically test it. The search space is en

The point is that given a solution to protein folding, we can then compare that solution with current theory and even physically test it. The search space is enormous but individual solutions are physically deterministic. This is a good application of ML since there is an independent “check” on its work. And it’s hard to call it “the end of theory” when theory is still tightly coupled with the system, just at the back end instead of the front end. That is not true of many applications of ML, like Facebook, which simply spit out solutions at scale with no way to independently check them. We should not think the same way about all ML systems; there is a lot more to it than just the neural network.

PaulDavisThe1st 5y ago
How is theory still involved? You don't use theory to check the predictions AlphaFold makes, you use molecular structure determination (x-ray crystalography, MRI, other techniques). Of course, those involve "theory", but not theories about protein folding.
- RandomLensman 5y ago
  For me, theory enables this to actually work in the sense that we know that structures are not random, i.e. there is some way to predict them and it is inherent in the composition (hand waving). If there is no theory linking input and output then predictions could just randomly stop working, for example.
  - PaulDavisThe1st 5y ago
    This is just simply incorrect. Theory is not involved in this. We know that a given protein will always (more or less) fold into the same configuration every time, generally on their own. We know this by doing experiments in which the protein is denatured (heated to break internal covalent and some ionic bonds, and then left to anneal (cool down), and then inspected at the atomic level for the resulting structure. They always fold back to the same shape. This is an experimental determination, not a theoretical one. Nobody was ever successful at devising any comprehensive theory that explained how they did this, though they of course identified many different elements that are likely involved in some way (hydrophobicity, local charge, possible compactness and many more). But there is (currently) no theory that connects protein amino acid sequence to structure, which is why AlphaFold was such a huge deal. It makes the connection (somehow), without any theory builtin, and without any theory to explain. In fact, there is not even a theory that requires that they always fold into the same shape.
    - RandomLensman 5y ago
      You are misunderstanding me. There is theory about how atoms etc. interact. We cannot use that to predict shape (at present) but at the same time there is no force etc. missing as far as our current understanding is concerned (at most basic level no physics seem to missing). So predictions seem at least possible or rather are not blocked. On the other hand, trying to use an AI to make predictions which atom of a radioactive element was to decay next would run afoul of current theories.
      - PaulDavisThe1st 5y ago
        People have worked on "theory-based" protein structure prediction for 35-40 years. It essentially went nowhere. It is theoretically possible? Probably. Does it have anything to do with how AlphaFold works? no. Does it have anything to do with verifying AlphaFold's predictions? no.
        RandomLensman 5y ago
        I never claimed it has anything to do with verifying the predictions. I am saying it allows such predictions.
        PaulDavisThe1st 5y ago
        But it doesn't! It isn't theory that led us to notice that (almost all) proteins fold naturally into the same shape every time they are denatured and annealed. It was simple experimentation. The attempts to create a theory of how that happens have been measured by the success of those attempted theories to make successful structure predictions. They have failed (pretty dismally in most cases). So there is no theory that allows us to make such predictions. We simply have experimental evidence that proteins can adopt their "normal" structure by themselves, essentially every time. We have no functioning theory of how they do this, and no way to use this non-existent theory to make predictions.
        5y ago

PaulDavisThe1st 5y ago

How is theory still involved? You don't use theory to check the predictions AlphaFold makes, you use molecular structure determination (x-ray crystalography, MRI, other techniques). Of course, those involve "theory", but not theories about protein folding.

RandomLensman 5y ago
For me, theory enables this to actually work in the sense that we know that structures are not random, i.e. there is some way to predict them and it is inherent in the composition (hand waving). If there is no theory linking input and output then predictions could just randomly stop working, for example.
- PaulDavisThe1st 5y ago
  This is just simply incorrect. Theory is not involved in this. We know that a given protein will always (more or less) fold into the same configuration every time, generally on their own. We know this by doing experiments in which the protein is denatured (heated to break internal covalent and some ionic bonds, and then left to anneal (cool down), and then inspected at the atomic level for the resulting structure. They always fold back to the same shape. This is an experimental determination, not a theoretical one. Nobody was ever successful at devising any comprehensive theory that explained how they did this, though they of course identified many different elements that are likely involved in some way (hydrophobicity, local charge, possible compactness and many more). But there is (currently) no theory that connects protein amino acid sequence to structure, which is why AlphaFold was such a huge deal. It makes the connection (somehow), without any theory builtin, and without any theory to explain. In fact, there is not even a theory that requires that they always fold into the same shape.
  - RandomLensman 5y ago
    You are misunderstanding me. There is theory about how atoms etc. interact. We cannot use that to predict shape (at present) but at the same time there is no force etc. missing as far as our current understanding is concerned (at most basic level no physics seem to missing). So predictions seem at least possible or rather are not blocked. On the other hand, trying to use an AI to make predictions which atom of a radioactive element was to decay next would run afoul of current theories.
    - PaulDavisThe1st 5y ago
      People have worked on "theory-based" protein structure prediction for 35-40 years. It essentially went nowhere. It is theoretically possible? Probably. Does it have anything to do with how AlphaFold works? no. Does it have anything to do with verifying AlphaFold's predictions? no.
      - RandomLensman 5y ago
        I never claimed it has anything to do with verifying the predictions. I am saying it allows such predictions.
        PaulDavisThe1st 5y ago
        But it doesn't! It isn't theory that led us to notice that (almost all) proteins fold naturally into the same shape every time they are denatured and annealed. It was simple experimentation. The attempts to create a theory of how that happens have been measured by the success of those attempted theories to make successful structure predictions. They have failed (pretty dismally in most cases). So there is no theory that allows us to make such predictions. We simply have experimental evidence that proteins can adopt their "normal" structure by themselves, essentially every time. We have no functioning theory of how they do this, and no way to use this non-existent theory to make predictions.
        5y ago