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

PLoS Comput Biol. 2017 Dec 27;13(12):e1005905. doi: 10.1371/journal.pcbi.1005905. eCollection 2017 Dec.

Abstract

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.

Publication types

  • Research Support, Non-U.S. Gov't
  • Validation Study

MeSH terms

  • Algorithms*
  • Computational Biology
  • Computer Simulation
  • Crystallography, X-Ray
  • Models, Molecular
  • Molecular Docking Simulation
  • Molecular Dynamics Simulation
  • Peptide Fragments / chemistry
  • Protein Conformation
  • Protein Interaction Mapping / statistics & numerical data*
  • Software

Substances

  • Peptide Fragments

Grants and funding

This work was supported by the European Research Council under the ERC Grant Agreement [310873] (to OSF), the USA-Israel Binational Science Foundation [2009418] (to OSF & DK), and NSF grants DBI 1458509 and AF 1527292 (to DK). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.