alt Hacker News> Presumably, if AlphaFold is finding the relationship, there's some information preserved at the sequence level
This is not my area of expertise, and maybe I'm misunderstanding this, but I thought that what AlphaFold does is extrapolate a structure from the sequence. The actual relationship with the other existing proteins would have been found by the investigators through other, more traditional means (like the 3D search you mentioned).
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This is a very big misconception about AlphaFold. It's not generating a structure totally de novo from sequencing. Instead it's primarily finding relationships on the sequence level to other solved structures. If those structure/sequence relationships didn't exist somewhere, AF wouldn't work because it doesn't really have much information about protein folding from first principles. There are some small de novo elements, but nothing really groundbreaking. Where AF's true strength lies is in it's ability to detect relationships we have been unable to detect with any other method.
I'm not sure about that. The way AlphaFold works involves transforming the protein from a vector space representing the sequence to a different vector space representing the folded structure and back again as it performs iterative refinement. Presumably you could perform a comparison in the structure space to find homologs that have completely different sequences - they would just have a high cosine similarity.
Checking sub-regions of the structure would be more difficult, but depending on how the structural representation works it could just be computationally intensive.