Matching protein surface structural patches for high-resolution blind peptide docking

Alisa Khramushin, Ziv Ben-Aharon, Tomer Tsaban, Julia K. Varga, Orly Avraham, Ora Schueler-Furman*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

9 Scopus citations

Abstract

Peptide docking can be perceived as a subproblem of protein-protein docking. However, due to the short length and flexible nature of peptides, many do not adopt one defined conformation prior to binding. Therefore, to tackle a peptide docking problem, not only the relative orientation, but also the bound conformation of the peptide needs to be modeled. Traditional peptide-centered approaches use information about peptide sequences to generate representative conformer ensembles, which can then be rigid-body docked to the receptor. Alternatively, one may look at this problem from the viewpoint of the receptor, namely, that the protein surface defines the peptidebound conformation. Here, we present PatchMAN (Patch-Motif AligNments), a global peptide-docking approach that uses structural motifs to map the receptor surface with backbone scaffolds extracted from protein structures. On a nonredundant set of protein-peptide complexes, starting from free receptor structures, PatchMAN successfully models and identifies near-native peptide-protein complexes in 58%/ 84% within 2.5 A/5 A interface backbone RMSD, with corresponding sampling in 81%/100% of the cases, outperforming other approaches. PatchMAN leverages the observation that structural units of peptides with their binding pocket can be found not only within interfaces, but also within monomers. We show that the bound peptide conformation is sampled based on the structural context of the receptor only, without taking into account any sequence information. Beyond peptide docking, this approach opens exciting new avenues to study principles of peptide-protein association, and to the design of new peptide binders. PatchMAN is available as a server at https://furmanlab.cs.huji.ac.il/patchman/.

Original languageAmerican English
Article numbere2121153119
JournalProceedings of the National Academy of Sciences of the United States of America
Volume119
Issue number18
DOIs
StatePublished - 3 May 2022

Bibliographical note

Publisher Copyright:
© 2022 National Academy of Sciences. All rights reserved.

Keywords

  • peptide docking
  • protein structure
  • structural motifs
  • structure matching
  • surface complementation

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