General Prediction of Peptide-MHC Binding Modes Using Incremental Docking: A Proof of Concept

Dinler A Antunes,Lydia E Kavraki,Didier Devaurs,Gregory Lizée,Mark Moll

doi:10.1038/s41598-018-22173-4

Dinler A Antunes, Lydia E Kavraki + Show 3 more

Open Access

https://doi.org/10.1038/s41598-018-22173-4

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Abstract

The class I major histocompatibility complex (MHC) is capable of binding peptides derived from intracellular proteins and displaying them at the cell surface. The recognition of these peptide-MHC (pMHC) complexes by T-cells is the cornerstone of cellular immunity, enabling the elimination of infected or tumoral cells. T-cell-based immunotherapies against cancer, which leverage this mechanism, can greatly benefit from structural analyses of pMHC complexes. Several attempts have been made to use molecular docking for such analyses, but pMHC structure remains too challenging for even state-of-the-art docking tools. To overcome these limitations, we describe the use of an incremental meta-docking approach for structural prediction of pMHC complexes. Previous methods applied in this context used specific constraints to reduce the complexity of this prediction problem, at the expense of generality. Our strategy makes no assumption and can potentially be used to predict binding modes for any pMHC complex. Our method has been tested in a re-docking experiment, reproducing the binding modes of 25 pMHC complexes whose crystal structures are available. This study is a proof of concept that incremental docking strategies can lead to general geometry prediction of pMHC complexes, with potential applications for immunotherapy against cancer or infectious diseases.

Highlights

Since a given class I major histocompatibility complex (MHC) molecule can only bind a subset of existing peptides[4], and since viral proteins have high mutation rates, MHC diversity became essential for the survival of the host population[1]
We report both Cα Root Mean Square Deviation (RMSD) and all-atom RMSD for our re-docking experiment, which was conducted on a structurally diverse dataset of pMHC complexes (Supplementary Table S1)
We demonstrate that an incremental meta-docking approach can predict the binding modes of large peptide ligands bound to MHC receptors

Summary

Introduction

Since a given class I MHC molecule can only bind a subset of existing peptides[4], and since viral proteins have high mutation rates (yielding ever-changing peptide pools), MHC diversity became essential for the survival of the host population[1]. Peptides are known to be very flexible ligands[24]; binding mode prediction of even small peptides, composed of up to 5 amino acids (which means around 24 internal DoFs), can be challenging for available docking methods[25,26] This limitation makes the structural prediction of pMHC complexes an impossible task for most docking tools, since a typical MHC-binder is a peptide composed of 8 to 11 amino acids (which translates to more than 30 internal DoFs). Despite promising results on a small number of known pMHC complexes, the choice of a more specific scoring function and the assumptions on the location of the peptide’s terminal amino acid residues raise questions about the generality of the method towards less prevalent MHC allotypes

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