title: A unified conformational selection and induced fit approach to protein-peptide docking.
abstract: Protein-peptide interactions are vital for the cell. They mediate, inhibit or serve as structural components in nearly 40% of all macromolecular interactions, and are often associated with diseases, making them interesting leads for protein drug design. In recent years, large-scale technologies have enabled exhaustive studies on the peptide recognition preferences for a number of peptide-binding domain families. Yet, the paucity of data regarding their molecular binding mechanisms together with their inherent flexibility makes the structural prediction of protein-peptide interactions very challenging. This leaves flexible docking as one of the few amenable computational techniques to model these complexes. We present here an ensemble, flexible protein-peptide docking protocol that combines conformational selection and induced fit mechanisms. Starting from an ensemble of three peptide conformations (extended, a-helix, polyproline-II), flexible docking with HADDOCK generates 79.4% of high quality models for bound/unbound and 69.4% for unbound/unbound docking when tested against the largest protein-peptide complexes benchmark dataset available to date. Conformational selection at the rigid-body docking stage successfully recovers the most relevant conformation for a given protein-peptide complex and the subsequent flexible refinement further improves the interface by up to 4.5 Å interface RMSD. Cluster-based scoring of the models results in a selection of near-native solutions in the top three for ∼75% of the successfully predicted cases. This unified conformational selection and induced fit approach to protein-peptide docking should open the route to the modeling of challenging systems such as disorder-order transitions taking place upon binding, significantly expanding the applicability limit of biomolecular interaction modeling by docking.
authors.affiliation: Computational Structural Biology Group, Bijvoet Center for Biomolecular Research, Faculty of Science - Chemistry, Utrecht University, Utrecht, The Netherlands.
authors.forename: Mikael
authors.initials: M
authors.lastname: Trellet
authors.forename: Adrien S J
authors.initials: AS
authors.lastname: Melquiond
authors.forename: Alexandre M J J
authors.initials: AM
authors.lastname: Bonvin
mesh_terms: D019985:Benchmarking; D016000:Cluster Analysis; D030562:Databases, Protein; D062105:Molecular Docking Simulation; D010455:Peptides / Q000737:chemistry* / Q000378:metabolism*; D011485:Protein Binding; D011487:Protein Conformation; D011506:Proteins / Q000737:chemistry* / Q000378:metabolism*; D013379:Substrate Specificity
chemical_list: D010455:Peptides; D011506:Proteins