title: FlexPepDock lessons from CAPRI peptide-protein rounds and suggested new criteria for assessment of model quality and utility.
abstract: CAPRI rounds 28 and 29 included, for the first time, peptide-receptor targets of three different systems, reflecting increased appreciation of the importance of peptide-protein interactions. The CAPRI rounds allowed us to objectively assess the performance of Rosetta FlexPepDock, one of the first protocols to explicitly include peptide flexibility in docking, accounting for peptide conformational changes upon binding. We discuss here successes and challenges in modeling these targets: we obtain top-performing, high-resolution models of the peptide motif for cases with known binding sites but there is a need for better modeling of flanking regions, as well as better selection criteria, in particular for unknown binding sites. These rounds have also provided us the opportunity to reassess the success criteria, to better reflect the quality of a peptide-protein complex model. Using all models submitted to CAPRI, we analyze the correlation between current classification criteria and the ability to retrieve critical interface features, such as hydrogen bonds and hotspots. We find that loosening the backbone (and ligand) RMSD threshold, together with a restriction on the side chain RMSD measure, allows us to improve the selection of high-accuracy models. We also suggest a new measure to assess interface hydrogen bond recovery, which is not assessed by the current CAPRI criteria. Finally, we find that surprisingly much can be learned from rather inaccurate models about binding hotspots, suggesting that the current status of peptide-protein docking methods, as reflected by the submitted CAPRI models, can already have a significant impact on our understanding of protein interactions. Proteins 2017; 85:445-462. © 2016 Wiley Periodicals, Inc.
authors.affiliation: Department of Microbiology and Molecular Genetics, Institute for Medical Research Israel-Canada, Faculty of Medicine, the Hebrew University of Jerusalem, Israel.
authors.forename: Orly
authors.initials: O
authors.lastname: Marcu
authors.affiliation: Department of Microbiology and Molecular Genetics, Institute for Medical Research Israel-Canada, Faculty of Medicine, the Hebrew University of Jerusalem, Israel.
authors.forename: Emma-Joy
authors.initials: EJ
authors.lastname: Dodson
authors.affiliation: Department of Microbiology and Molecular Genetics, Institute for Medical Research Israel-Canada, Faculty of Medicine, the Hebrew University of Jerusalem, Israel.
authors.forename: Nawsad
authors.initials: N
authors.lastname: Alam
authors.affiliation: Department of Microbiology and Molecular Genetics, Institute for Medical Research Israel-Canada, Faculty of Medicine, the Hebrew University of Jerusalem, Israel.
authors.forename: Michal
authors.initials: M
authors.lastname: Sperber
authors.affiliation: Department of Applied Mathematics and Statistics, Stony Brooks University, Stony Brook, New York, 11794.
authors.forename: Dima
authors.initials: D
authors.lastname: Kozakov
authors.affiliation: University of Lille, CNRS UMR8576 UGSF, Lille, 59000, France.
authors.forename: Marc F
authors.initials: MF
authors.lastname: Lensink
authors.affiliation: Department of Microbiology and Molecular Genetics, Institute for Medical Research Israel-Canada, Faculty of Medicine, the Hebrew University of Jerusalem, Israel.
authors.forename: Ora
authors.initials: O
authors.lastname: Schueler-Furman
mesh_terms: D000465:Algorithms; D020816:Amino Acid Motifs; D019985:Benchmarking; D001665:Binding Sites; D019295:Computational Biology / Q000379:methods*; D018360:Crystallography, X-Ray; D006860:Hydrogen Bonding; D062105:Molecular Docking Simulation / Q000379:methods*; D010455:Peptides / Q000737:chemistry*; D011485:Protein Binding; D011487:Protein Conformation; D025941:Protein Interaction Mapping; D011506:Proteins / Q000737:chemistry*; D012107:Research Design; D012984:Software; D040681:Structural Homology, Protein; D013816:Thermodynamics
chemical_list: D010455:Peptides; D011506:Proteins
keywords: CAPRI; FlexPepDock; Peptide docking; binding hotspots; impact of low-accuracy models; model assessment