4 ms·

what has changed? I think people need more from a comment than blind trust.

dekhn 2y ago
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 arguing about the finer details of what it gets wrong is support for its value, not a detriment.
- timr 2y ago
  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 Rosetta, of course). Now it is a very confident theory that is used to make a slightly larger subset of predictions via a totally different method, but still fails at the ones we don't know about. Vive la change!
  - dekhn 2y ago
    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.
    - flobosg 2y ago
      > and used just tiny fragments from the PDB 3-mers and 9-mers, if I recall correctly. The fragment-based approach helped immensely with cutting down the conformational search space. The secondary structure of those fragments was enough to make educated guesses of the protein backbone’s, at a time where ab initio force field predictions struggled with it.
      - timr 2y ago
        Yes, Rosetta did monte carlo substitution of 9-mers, followed by a refinement phase with 3-mers. Plus a bunch of other stuff to generate more specific backbone "moves" in weird circumstances. In order to create those fragment libraries, there was a step involving generation of multiple-sequence alignments, pruning the alignments, etc. Rosetta used sequence homology to generate structure. This wasn't a wild, untested theory.
        flobosg 2y ago
        > Rosetta used sequence homology Rosetta used remote sequence homology to generate the MSAs and find template fragments, which at the time was innovative. A similar strategy is employed for AlphaFold’s MSAs containing the evolutionary couplings.
        timr 2y ago
        Yep. That's what I'm saying.
        dekhn 2y ago
        I don't know that I agree that fragment libraries use sequence homology. From my understanding of it, homology implies an actual evolutionary relationship. Wheras fragment libraries instead are agnostic and instead seem to be based on the idea that short fragments of non-related proteins can match up in sequence and structure space. Nobody looks at 3-mers and 9-mers in homology modelling; it's typically well over 25 amino acids long, and there is usually a plausible whole-domain (in the SCOP terminology). But, the protein field has always played loose with the term "homology".

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 arguing about the finer details of what it gets wrong is support for its value, not a detriment.

timr 2y ago
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 Rosetta, of course). Now it is a very confident theory that is used to make a slightly larger subset of predictions via a totally different method, but still fails at the ones we don't know about. Vive la change!
- dekhn 2y ago
  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.
  - flobosg 2y ago
    > and used just tiny fragments from the PDB 3-mers and 9-mers, if I recall correctly. The fragment-based approach helped immensely with cutting down the conformational search space. The secondary structure of those fragments was enough to make educated guesses of the protein backbone’s, at a time where ab initio force field predictions struggled with it.
    - timr 2y ago
      Yes, Rosetta did monte carlo substitution of 9-mers, followed by a refinement phase with 3-mers. Plus a bunch of other stuff to generate more specific backbone "moves" in weird circumstances. In order to create those fragment libraries, there was a step involving generation of multiple-sequence alignments, pruning the alignments, etc. Rosetta used sequence homology to generate structure. This wasn't a wild, untested theory.
      - flobosg 2y ago
        > Rosetta used sequence homology Rosetta used remote sequence homology to generate the MSAs and find template fragments, which at the time was innovative. A similar strategy is employed for AlphaFold’s MSAs containing the evolutionary couplings.
        timr 2y ago
        Yep. That's what I'm saying.
      - dekhn 2y ago
        I don't know that I agree that fragment libraries use sequence homology. From my understanding of it, homology implies an actual evolutionary relationship. Wheras fragment libraries instead are agnostic and instead seem to be based on the idea that short fragments of non-related proteins can match up in sequence and structure space. Nobody looks at 3-mers and 9-mers in homology modelling; it's typically well over 25 amino acids long, and there is usually a plausible whole-domain (in the SCOP terminology). But, the protein field has always played loose with the term "homology".