Mutation prioritization using structure-based methods To benchmark the structure-based method on the BO performance, the following procedure was used: starting from a single protein-peptide complex, each residue of the co-crystallized peptide was alternatively mutated to the 20 standard amino acids, and a protein-peptide interaction score was predicted upon the mutation using either the Rosetta Flex ∆∆G or FlexPepDock, or FoldX method. The initial batch was then constituted based on the predicted protein-peptide interaction scores (∆∆Gs from Rosetta Flex ∆∆G and FoldX, and reweighted scores from Rosetta FlexPepDock), selecting the 96 peptides with the lowest scores. During BO, peptide lengths remained fixed.