Best way to do protein structure guided similarity search?

Question

[Mark]

I don't have much as much protein level analysis as I do DNA analysis, so I'm not really sure what the best tools or workflows currently out there are for this, but the problem is fairly straight forward.

I'm looking for a workflow that basically acts like BLAST, but instead of looking for sequence similarity, it check for gene product structure similarity.

Basically I have a many variants of a certain gene and I want to check if this new organisms genome potentially encodes for a protein that is structurally similar to any of these variants. I could use BLAST to achieve this task as well but with modern tools I'm sure that it's possible to do this on a structural level too and I want to be thorough.

Does anyone have any advice?

[Joe]

There are tools that sort of do this with sequence information still.

I would consider looking at HMM based methods for starters (hhsuite is really good). This intrinsically captures domain structure similarly in very distantly related domains/proteins (as low as even 20-30% sequence similarity).

This doesnt always capture the 'edge case' of convergent evolution of structures but in my experience works pretty well nevertheless.

If memory serves there are some TM-align/RMSD-based search methods but I'm blanking on what they are at the moment.

Worth bearing in mind that (save for alphafold simulations) there are a lot more sequences with good sequence data than there are resolved protein structures.

[lieven.sterck]

Something along the line of working with HMMs: you could also consider using PSI-BLAST. (though equally non-modern like HMM searches :) )

[Dunois]

Foldseek perhaps? They have a server for it too: https://search.foldseek.com/ .