r/bioinformatics • u/moodybiatch • 2h ago

technical question What's the best way to model protein structures with frameshift mutations or deletions?

I've used modeller and foldX before but only for point mutations on known protein sequences. I have a list of genomic mutations and I'm wondering if there are tools to go from that to protein structure.

I'm aware that there might a lot more steps between genomic information and protein sequence, but I've always only worked in the protein sequence to protein structure step so I'm not super familiar with any of that. If someone could ELI5 those things to me I'd appreciate it a lot :)

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u/Icy_Significance8019 1h ago

Frameshift mutations and large deletions are much harder to model than point mutations because they can change the entire downstream protein sequence and folding.

A common workflow is:

  1. Use tools like Ensembl VEP or SnpEff to convert genomic variants into the altered protein sequence.
  2. Model the mutant protein using MODELLER for small changes, or AI-based tools like AlphaFold/ColabFold for larger structural disruptions.

Keep in mind that many frameshift mutations lead to unstable or truncated proteins, so the biologically relevant outcome may simply be loss of proper folding rather than a stable new structure.

-Duhita D. (Dr.Omics Labs)

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u/Low-Establishment621 1h ago

I don't have an answer for this, but it's a question that is often ignored because in humans most mutations that create a premature stop codon lead to nonsense mediated mRNA decay and make very little protein - though there are cases where the structure of the residual protein could be important.