3 ms·

"Jeez. Clickbait title, tons of fallacy, like goalpost moving." Pretty much everything in the post is true, the title isn't clickbait, and I didn't see any fal

by timr 6y ago

"Jeez. Clickbait title, tons of fallacy, like goalpost moving." Pretty much everything in the post is true, the title isn't clickbait, and I didn't see any fallacy. It's only "goalpost moving" if you confused the location of the goalposts in the first place. For the record: I have worked on protein folding, I did a PhD in a closely related area, and I work in computational structural biology professionally now. The OP is saying that the general problem isn't solved, and provided (IMO factual, true) explanations why there's still a long way to go. Arguing that it's OK for some uses (which is what you're doing) is true, but not a rebuttal. Maybe it's possible to use this method to come up with models "good enough" for rigid-body docking, or to get the overall idea of a fold. But it's also true that these structures aren't going to be good enough for any kind of drug discovery, which is what TFA says.

dnautics 6y ago
I did my PhD program at one the world's foremost structural biology program at the time (TSRI). I've solved loose structures of metastable peptides in NMR (by hand-- https://pubs.acs.org/doi/abs/10.1021/bi800828u https://pubs.acs.org/doi/abs/10.1021/bi800828u, those assignments were painstakingly conducted by yours truly with assistance from Jane Dyson). I've done thousands of crystal drops with insulin to try to cocrystalize it (and failed; the x-ray structure I got did not have the cocrystal partner). I provided the critical insight for the prep enabled EM structure solved by the postdoc at the bench next to me: https://www.nature.com/articles/nature04339 https://www.nature.com/articles/nature04339 . I'm pretty familiar with many aspects of the world of structural biology, but more importantly it's never been my primary - I've always been a consumer of the results first, a practitioner of it second. It is my judgement that if you presented these results in 2003 anyone would have said "the protein folding problem has been solved". Nobody then expected "the solution to protein folding" to solve every single protein, and it's silly to now. If you're complaining about the 33% error rate, you don't know enough about ML to realize that that gap is going to get closed, and rapidly. My argument is that it is "good enough for the uses that are in the domain of protein folding". There are a lot of things that are adjacent to protein folding (enzyme pocket analysis .e.g), but they never have been considered to protein folding per se.
- timr 6y ago
  So you're a structural biologist. Good for you? I'm not sure how it affects that substance of the argument you're making. I'm not trying to argue from authority here -- I'm pointing out that I have direct experience in this specific area, just so that you know I'm not some random commenter. "It is my judgement that if you presented these results in 2003 anyone would have said "the protein folding problem has been solved"." Your judgment is your own. At the very least, your use of the word "anyone" should give you pause. "Nobody then expected "the solution to protein folding" to solve every single protein, and it's silly to now." Not the argument I'm making. "If you're complaining about the 33% error rate, you don't know enough about ML to realize that that gap is going to get closed, and rapidly." Not the argument I'm making. "My argument is that it is "good enough for the uses that are in the domain of protein folding"." I have no idea what that means. Uses "in the domain of protein folding" are equivalent to uses "in the domain of structural biology". So obviously, it depends on the quality of the structure being generated. "There are a lot of things that are adjacent to protein folding (enzyme pocket analysis .e.g), but they never have been considered to protein folding per se." You seem to have some internal dialogue where there is a field called "protein folding", where there is an unambiguous threshold for success that has now been crossed. There is no such field, and there is no such threshold. Are these structures good enough to do some kinds of things, like structural genomics or docking? I dunno...maybe? Are they good enough to do structure-based drug design? Not from what I've seen. TFA seems to be saying the same thing, and your comment was that TFA is just wildly wrong, which seemed...unfair, at best.

by timr 6y ago

dnautics 6y ago

I did my PhD program at one the world's foremost structural biology program at the time (TSRI). I've solved loose structures of metastable peptides in NMR (by hand-- https://pubs.acs.org/doi/abs/10.1021/bi800828u https://pubs.acs.org/doi/abs/10.1021/bi800828u, those assignments were painstakingly conducted by yours truly with assistance from Jane Dyson). I've done thousands of crystal drops with insulin to try to cocrystalize it (and failed; the x-ray structure I got did not have the cocrystal partner). I provided the critical insight for the prep enabled EM structure solved by the postdoc at the bench next to me: https://www.nature.com/articles/nature04339 https://www.nature.com/articles/nature04339 . I'm pretty familiar with many aspects of the world of structural biology, but more importantly it's never been my primary - I've always been a consumer of the results first, a practitioner of it second. It is my judgement that if you presented these results in 2003 anyone would have said "the protein folding problem has been solved". Nobody then expected "the solution to protein folding" to solve every single protein, and it's silly to now. If you're complaining about the 33% error rate, you don't know enough about ML to realize that that gap is going to get closed, and rapidly. My argument is that it is "good enough for the uses that are in the domain of protein folding". There are a lot of things that are adjacent to protein folding (enzyme pocket analysis .e.g), but they never have been considered to protein folding per se.

timr 6y ago
So you're a structural biologist. Good for you? I'm not sure how it affects that substance of the argument you're making. I'm not trying to argue from authority here -- I'm pointing out that I have direct experience in this specific area, just so that you know I'm not some random commenter. "It is my judgement that if you presented these results in 2003 anyone would have said "the protein folding problem has been solved"." Your judgment is your own. At the very least, your use of the word "anyone" should give you pause. "Nobody then expected "the solution to protein folding" to solve every single protein, and it's silly to now." Not the argument I'm making. "If you're complaining about the 33% error rate, you don't know enough about ML to realize that that gap is going to get closed, and rapidly." Not the argument I'm making. "My argument is that it is "good enough for the uses that are in the domain of protein folding"." I have no idea what that means. Uses "in the domain of protein folding" are equivalent to uses "in the domain of structural biology". So obviously, it depends on the quality of the structure being generated. "There are a lot of things that are adjacent to protein folding (enzyme pocket analysis .e.g), but they never have been considered to protein folding per se." You seem to have some internal dialogue where there is a field called "protein folding", where there is an unambiguous threshold for success that has now been crossed. There is no such field, and there is no such threshold. Are these structures good enough to do some kinds of things, like structural genomics or docking? I dunno...maybe? Are they good enough to do structure-based drug design? Not from what I've seen. TFA seems to be saying the same thing, and your comment was that TFA is just wildly wrong, which seemed...unfair, at best.