High-resolution global peptide-protein docking using fragments-based PIPER-FlexPepDock

Peptide-protein interactions contribute a significant fraction of the protein-protein interactome. Accurate modeling of these interactions is challenging due to the vast conformational space associated with interactions of highly flexible peptides with large receptor surfaces. To address this challenge we developed a fragment based high-resolution peptide-protein docking protocol. By streamlining the Rosetta fragment picker for accurate peptide fragment ensemble generation, the PIPER docking algorithm for exhaustive fragment-receptor rigid-body docking and Rosetta FlexPepDock for flexible full-atom refinement of PIPER docked models, we successfully addressed the challenge of accurate and efficient global peptide-protein docking at high-resolution with remarkable accuracy, as validated on a small but representative set of peptide-protein complex structures well resolved by X-ray crystallography. Our approach opens up the way to high-resolution modeling of many more peptide-protein interactions and to the detailed study of peptide-protein association in general. PIPER-FlexPepDock is freely available to the academic community as a server at http://piperfpd.furmanlab.cs.huji.ac.il.Author summary: Peptide-protein interactions are crucial components of various important biological processes in living cells. High-resolution structural information of such interactions provides insight about the underlying biophysical principles governing the interactions, and a starting point for their targeted manipulations. Accurate docking algorithms can help fill the gap between the vast number of these interactions and the small number of experimentally solved structures. However, the accuracies of the existing protocols have been limited, in particular for ab initio docking when no information about the peptide beyond its sequence is available. Here we introduce PIPER-FlexPepDock, a fragment-based global docking protocol for high-resolution modeling of peptide-protein interactions. Integration of accurate and efficient representation of the peptide using fragment ensembles, their fast and exhaustive rigid-body docking, and their subsequent accurate flexible refinement, enables peptide-protein docking of remarkable accuracy. The validation on a representative benchmark set of crystallographically solved high-resolution peptide-protein complexes demonstrates significantly improved performance over all existing docking protocols. This opens up the way to the modeling of many more peptide-protein interactions, and to a more detailed study of peptide-protein association in general.