How to estimate the stability of a protein complex?

Question

[Qroid]

From co-fractionation experiments we've identified a subset of known mammalian protein complexes as interesting, approximately 50 CORUM complexes. We'd like to do an enrichment-style analysis to know more about them. One question I have is whether these complexes are particularly stable (since stable complexes should be biased towards detection). However I don't know how to approach finding the stability of a protein complex.

Given a list of proteins in a complex, are there any conventional, in silico ways to estimate the stability of that protein complex? If not, have people published numbers for the stability of well-known complexes?

I'm okay being vague about the definition of "stability" since I'll be satisfied with an answer that uses any definition of it.

(This question was originally asked on biology.stackexchange but didn't get an answer.)

Answer 1

[Jean-Karim Heriche]

There's no easy answer because complex stability hasn't been systematically studied and can be defined in different ways and is also subject to many influences. The notion of stability you want is one that is relevant for the type of experiment you've used to derive your data. For example detection is biased towards stable complexes in AP-MS experiments but that may not be the case if you derive complexes from some other type of experiments like yeast two-hybrid. Note also that it is usually assumed that complexes found in AP-MS experiments are stable. This is without even considering the definition of what constitutes a complex (see for example here).
Anyway, here are some ideas:
- use complex member protein stability as a proxy, the idea being that if a member is unstable, then the complex would also be unstable (probably not true in many cases though because being in a complex may stabilize a protein),
- use information on the protein-protein interfaces e.g. binding energy,
- compare complexes found in AP-MS experiments with and without cross-linking (which would stabilize transient interactions).
- train a machine learning model to predict stability based on a training data set of curated complexes.

[Qroid]

That's very helpful. Using binding energy sounds appealing. Would you recommend something like this paper (https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3375440/ )? From the abstract: "We present an energy function for predicting binding free energies of protein–protein complexes, using the three-dimensional structures of the complex and unbound proteins as input."

Also, complexes are identified by co-fractionation (co-elution, protein correlation profiling). I edited the question to reflect this.

[Jean-Karim Heriche]

I haven't read this paper but this looks like what I was thinking about.

[Qroid]

Thanks again. I asked a followup question here. Wasn't sure if if I should ask in the comments or not.

[GenoMax]

It new question is a direct follow-up for the answer it would be appropriate to ask it here.

Since you have it cross-linked these two threads it should be fine.