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

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.

HLA-Arena: A Customizable Environment for the Structural Modeling and Analysis of Peptide-HLA Complexes for Cancer Immunotherapy

“… 8 The second, called DINC, can incrementally dock a peptide in the binding site and does not require any template ( Fig 2 ; Appendix). 9 , 10 , 21 Each approach has different strengths and limitations and can therefore suit various user needs, depending on the task at hand. For instance, its speed makes APE-Gen better suited for large-scale modeling and structure-based virtual screening.…”

“… 9 , 22 Both APE-Gen and DINC have been validated in previous publications. 8 , 10 , 23 In this report, we present a unified environment that facilitates the use of APE-Gen, DINC, and other tools for various research applications.…”

“… 8 We have also developed a meta-docking approach, called DINC, which allows prediction of binding modes of pHLA complexes. 9 , 10 …”

Highly conserved hemagglutinin peptides of H1N1 influenza virus elicit immune response

“…Efficient binding of HLA molecules to the peptides is a critical step towards the successful induction of peptide-mediated T-cell-mediated adaptive immune response (Blum et al 2013). Thus, analysing peptide-HLA interaction shall give an approximate idea of immunogenicity (Antunes et al 2018).…”

pMHC Structural Comparisons as a Pivotal Element to Detect and Validate T-Cell Targets for Vaccine Development and Immunotherapy—A New Methodological Proposal

“…It hinders the prediction of the binding core, hampering the extraction of more subtle electrostatic potential footprints, for example. Some methods are improving the benchmarks, and we hope that our pipeline will be used for this important purpose [26][27][28][29]. The knowledge of which viral peptides are involved in a specific infection response and its contribution to the disease progression is essential for an understanding of disease control and further pathogen elimination.…”