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

Nawsad Alam,Dima Kozakov,Oriel Goldstein,Kathryn A Porter,Ora Schueler-Furman,Bing Xia,Roland L Dunbrack

doi:10.1371/journal.pcbi.1005905

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.

Highlights

Proteins are the workhorses inside living cells, and interactions among them are critical for various important biological processes [1]
The challenges associated with the global docking of flexible peptides have been addressed in different ways, by reducing the conformational space to be sampled both for the internal degrees of freedom of the peptide as well as its rigid-body orientations on the receptor surface
The recently published intrinsically disordered proteins (IDPs)-LZerD protocol models the binding of long disordered segments to structured proteins using the Rosetta fragment picker protocol [22] to generate fragments of 9-residue overlapping windows followed by LZerD [23] rigid-body docking and molecular dynamics refinement [17]

Summary

Introduction

Proteins are the workhorses inside living cells, and interactions among them are critical for various important biological processes [1]. The MDockPep protocol [16] uses peptide sequence similarity to extract fragments from high resolution protein structures, which are further refined using MODELLER [20] to generate plausible peptide conformations, and docked onto the receptor using rigid-body docking and flexible docking with AutoDock Vina [21]. We have recently advanced a novel, global motif-based peptide fragment docking approach, PeptiDock [24], in which peptide binding motif information rather than secondary structure propensity is used to extract fragments from the Protein Data Bank (PDB [25]), which are docked to the receptor using PIPER rigid body docking [26], followed by minimization using CHARMM [27]

Methods

Results

Discussion

Conclusion