3 ms·

Honest question: since AlphaFold doesn't really _solve_ the protein folding problem (it's NP-complete after all), but only _approximates_ solutions very well, w

by Cas9 5y ago

Honest question: since AlphaFold doesn't really _solve_ the protein folding problem (it's NP-complete after all), but only _approximates_ solutions very well, what are the real impacts of this? Isn't a good approximation of a protein enough to cause unexpected problems? How do we know that an approximate structure will perform the same as the correct solution?

Ultimatt 5y ago
There is a lot of bias in the chat here from a more chemistry and pharma slant. If you ignore this AlphaFold solves in a very meaningful way the problem blocking a lot of science investigation. For comparative and evolutionary analysis structure is far more conserved than sequence. Especially in things like viruses or anything with a high rate of reproduction like bacteria. Just knowing the general fold or overall structure is enough to do structural alignment and tell if two genes are related on that basis, even if their genomic sequence is completely dissimilar. Large groups of researchers rely on sequence homology built from sequences of known structure. But AlphaFold works well in new sequence space to far more accuracy than is needed. If we had an AlphaFold prediction for every known sequence suddenly the evolutionary relationships between all genes and even all species would be far clearer. This on its own unlocks a new foundation to reason about function and molecular interaction with a wholistic systems view without gaps in what we can know with some reasonable assurance. For an analogy think of the difference between having books in different languages describing objects. You know what some of the book in English might say but you dont even know if the book in Spanish is even talking about the same things. AlphaFold is like an AI that transforms all the books into picture books and now we can use image similarity or have one person look at all pictures.
- haihaibye 5y ago
  > even if their genomic sequence is completely dissimilar I think you mean amino acid homology? (due to synonymous mutations) I looked it up and you're right, protein structure/motifs are much more highly conserved than amino acid sequence https://humgenomics.biomedcentral.com/articles/10.1186/1479-7364-6-10#ref-CR3 https://humgenomics.biomedcentral.com/articles/10.1186/1479-...

by Cas9 5y ago

Ultimatt 5y ago

There is a lot of bias in the chat here from a more chemistry and pharma slant. If you ignore this AlphaFold solves in a very meaningful way the problem blocking a lot of science investigation. For comparative and evolutionary analysis structure is far more conserved than sequence. Especially in things like viruses or anything with a high rate of reproduction like bacteria. Just knowing the general fold or overall structure is enough to do structural alignment and tell if two genes are related on that basis, even if their genomic sequence is completely dissimilar. Large groups of researchers rely on sequence homology built from sequences of known structure. But AlphaFold works well in new sequence space to far more accuracy than is needed. If we had an AlphaFold prediction for every known sequence suddenly the evolutionary relationships between all genes and even all species would be far clearer. This on its own unlocks a new foundation to reason about function and molecular interaction with a wholistic systems view without gaps in what we can know with some reasonable assurance. For an analogy think of the difference between having books in different languages describing objects. You know what some of the book in English might say but you dont even know if the book in Spanish is even talking about the same things. AlphaFold is like an AI that transforms all the books into picture books and now we can use image similarity or have one person look at all pictures.

haihaibye 5y ago
> even if their genomic sequence is completely dissimilar I think you mean amino acid homology? (due to synonymous mutations) I looked it up and you're right, protein structure/motifs are much more highly conserved than amino acid sequence https://humgenomics.biomedcentral.com/articles/10.1186/1479-7364-6-10#ref-CR3 https://humgenomics.biomedcentral.com/articles/10.1186/1479-...