FlexPepDock lessons from CAPRI peptide–protein rounds and suggested new criteria for assessment of model quality and utility

Orly Marcu, Emma Joy Dodson, Nawsad Alam, Michal Sperber, Dima Kozakov, Marc F. Lensink, Ora Schueler-Furman*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

19 Scopus citations

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.

Original languageAmerican English
Pages (from-to)445-462
Number of pages18
JournalProteins: Structure, Function and Bioinformatics
Volume85
Issue number3
DOIs
StatePublished - 1 Mar 2017

Bibliographical note

Publisher Copyright:
© 2016 Wiley Periodicals, Inc.

Keywords

  • CAPRI
  • FlexPepDock
  • Peptide docking
  • binding hotspots
  • impact of low-accuracy models
  • model assessment

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