Prediction of Protein-Protein Interface Sequence Diversity Using Flexible Backbone Computational Protein Design

A major challenge in computational protein design is to identify functional sequences as top predictions. One reason for design failures is conformational plasticity, as proteins frequently change their conformation in response to mutations. To advance protein design, here we describe a method employing flexible backbone ensembles to predict sequences tolerated for a protein-protein interface. We show that the predictions are enriched in functional proteins when compared to a phage display screen quantitatively mapping the energy landscape for the interaction between human growth hormone and its receptor. Our model for structural plasticity is inspired by coupled side chain-backbone backrub motions observed in high-resolution protein crystal structures. Although the modeled structural changes are subtle, our results on predicting sequence plasticity suggest that backrub sampling may capture a sizable fraction of localized conformational changes that occur in proteins. The described method has implications for predicting sequence libraries to enable challenging protein engineering problems.