Rēs ipSAE loquuntur : What’s wrong with AlphaFold’s ipTM score and how to fix it

Abstract AlphaFold’s ipTM metric is used to predict the accuracy of structural predictions of protein-protein interactions (PPIs) and the probability that two proteins interact. Many AF2/AF3 users have experienced the phenomenon that if they trim full-length sequence constructs (e.g. from UniProt) to the interacting domains (or domain+peptide), their ipTM scores change, even though the structure prediction of the interaction is unchanged. The reason this happens is due to the mathematical formulation of ipTM in AF2/AF3, which scores the interactions of whole chains. When one chain is a single ordered domain but the other contains lots of disorder or irrelevant domains, ipTM is higher in the presence of those…