Comment by shpongled
2 years ago
> Comparing alphafold to conventional homology modeling is disingenuous at its most charitable interpretation.
It's really not - have you played around with AF at all? Made mutations to protein structures and asked it to model them? Go look up the crystal structures for important proteins like FOXA1 [1], AR [2], EWSR1 [3], etc (i.e. pretty much any protein target we really care about and haven't previously solved) and tell me with a straight face that AF has "solved" protein folding - it's just a fancy language model that's pattern matching to things it's already seen solved before.
signed, someone with a PhD in biochemistry.
[1] https://alphafold.ebi.ac.uk/entry/P55317 [2] https://alphafold.ebi.ac.uk/entry/P10275 [3] https://alphafold.ebi.ac.uk/entry/Q01844
I can see the loops in these structures. I dont see the problem. It still added a structure to every embl page, and people are free to judge the predictions themselves. For all I care (ostensibly as the end customer of these structures) I don’t mind having a low confidence structure for any arbitrary protein at all. It’s only marginally less useful to actual biology than full on X-ray structures anyway.
> It’s only marginally less useful to actual biology than full on X-ray structures anyway.
I'm not sure what you're implying here. Are you saying both types of structures are useful, but not as useful as the hype suggests, or that an X-Ray Crystal (XRC) and low confidence structures are both very useful with the XRC being marginally more so?
An XRC structure is great, but it's a very (very) long way from getting me to a drug. Observe the long history of fully crystalized proteins still lacking a good drug. Or this piece on the general failure of purely structure guided efforts in drug discovery for COVID (https://www.science.org/content/blog-post/virtual-screening-...). I think this tech will certainly be helpful, but for most problems I don't see it being better than a slightly-more-than-marginal gain in our ability to find medicines.
Edit: To clarify, if the current state of the field is "given a well understood structure, I often still can't find a good medicine without doing a ton of screening experiments" then it's hard to see how much this helps us. I can also see several ways in which a less than accurate structure could be very misleading.
FWIW I can see a few ways in which it could be very useful for hypothesis generation too, but we're still talking pretty early stage basic science work with lots of caveats.
Source: PhD Biochemist and CEO of a biotech.