Modeling beta-sheet peptide-protein interactions: Rosetta FlexPepDock in CAPRI rounds 38-45

Alisa Khramushin, Orly Marcu, Nawsad Alam, Orly Shimony, Dzmitry Padhorny, Emiliano Brini, Ken A. Dill, Sandor Vajda, Dima Kozakov*, Ora Schueler-Furman*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

8 Scopus citations

Abstract

Peptide-protein docking is challenging due to the considerable conformational freedom of the peptide. CAPRI rounds 38-45 included two peptide-protein interactions, both characterized by a peptide forming an additional beta strand of a beta sheet in the receptor. Using the Rosetta FlexPepDock peptide docking protocol we generated top-performing, high-accuracy models for targets 134 and 135, involving an interaction between a peptide derived from L-MAG with DLC8. In addition, we were able to generate the only medium-accuracy models for a particularly challenging target, T121. In contrast to the classical peptide-mediated interaction, in which receptor side chains contact both peptide backbone and side chains, beta-sheet complementation involves a major contribution to binding by hydrogen bonds between main chain atoms. To establish how binding affinity and specificity are established in this special class of peptide-protein interactions, we extracted PeptiDBeta, a benchmark of solved structures of different protein domains that are bound by peptides via beta-sheet complementation, and tested our protocol for global peptide-docking PIPER-FlexPepDock on this dataset. We find that the beta-strand part of the peptide is sufficient to generate approximate and even high resolution models of many interactions, but inclusion of adjacent motif residues often provides additional information necessary to achieve high resolution model quality.

Original languageAmerican English
Pages (from-to)1037-1049
Number of pages13
JournalProteins: Structure, Function and Bioinformatics
Volume88
Issue number8
DOIs
StatePublished - 1 Aug 2020

Bibliographical note

Publisher Copyright:
© 2020 Wiley Periodicals, Inc.

Keywords

  • CAPRI
  • FlexPepDock
  • Rosetta
  • beta sheet interactions
  • high-resolution modeling
  • peptide docking
  • peptide-protein interactions

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