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How T cell receptors interact with peptide-MHCs: A multiple steered molecular dynamics study

Authors

  • Michel A. Cuendet,

    1. Swiss Institute of Bioinformatics, Génopode, 1015 Lausanne, Switzerland
    2. Department of Chemistry, New York University, New York, New York 10003
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  • Vincent Zoete,

    1. Swiss Institute of Bioinformatics, Génopode, 1015 Lausanne, Switzerland
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  • Olivier Michielin

    Corresponding author
    1. Swiss Institute of Bioinformatics, Génopode, 1015 Lausanne, Switzerland
    2. Ludwig Institute for Cancer Research, Lausanne Branch, 1066 Epalinges, Switzerland
    3. Multidisciplinary Oncology Center, Centre Hospitalier Universitaire Vaudois, Rue du Bugnon 46, Switzerland
    • Swiss Institute of Bioinformatics, Génopode, 1015 Lausanne, Switzerland
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Abstract

The T-cell receptor (TCR) interaction with antigenic peptides (p) presented by the major histocompatibility complex (MHC) molecule is a key determinant of immune response. In addition, TCR-pMHC interactions offer examples of features more generally pertaining to protein-protein recognition: subtle specificity and cross-reactivity. Despite their importance, molecular details determining the TCR-pMHC binding remain unsolved. However, molecular simulation provides the opportunity to investigate some of these aspects. In this study, we perform extensive equilibrium and steered molecular dynamics simulations to study the unbinding of three TCR-pMHC complexes. As a function of the dissociation reaction coordinate, we are able to obtain converged H-bond counts and energy decompositions at different levels of detail, ranging from the full proteins, to separate residues and water molecules, down to single atoms at the interface. Many observed features do not support a previously proposed two-step model for TCR recognition. Our results also provide keys to interpret experimental point-mutation results. We highlight the role of water both in terms of interface resolvation and of water molecules trapped in the bound complex. Importantly, we illustrate how two TCRs with similar reactivity and structures can have essentially different binding strategies. Proteins 2011; © 2011 Wiley-Liss, Inc.

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