Protein stability models fail to capture epistatic interactions of double point mutations.

Protein stability is governed in part by epistatic interactions between energetically coupled residues. Prediction of these couplings represents the next frontier in protein stability modeling. In this work, we benchmark protein stability models on a large dataset of double point mutations and identify previously overlooked limitations in model design and evaluation. We also introduce several new strategies to improve modeling of epistatic couplings between protein point mutations.