Protein-peptide interactions adopt the same structural motifs as monomeric protein folds.

We compared the modes of interaction between protein-peptide interfaces and those observed within monomeric proteins and found surprisingly few differences. Over 65% of 731 protein-peptide interfaces could be reconstructed within 1 A RMSD using solely fragment interactions occurring in monomeric proteins. Interestingly, more than 80% of interacting fragments used in reconstructing a protein-peptide binding site were obtained from monomeric proteins of an entirely different structural classification, with an average sequence identity below 15%. Nevertheless, geometric properties perfectly match the interaction patterns observed within monomeric proteins. We show the usefulness of our approach by redesigning the interaction scaffold of nine protein-peptide complexes, for which five of the peptides can be modeled within 1 A RMSD of the original peptide position. These data suggest that the wealth of structural data on monomeric proteins could be harvested to model protein-peptide interactions and, more importantly, that sequence homology is no prerequisite.