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How T cell receptors interact with peptide‐MHCs: A multiple steered molecular dynamics study
Author(s) -
Cuendet Michel A.,
Zoete Vincent,
Michielin Olivier
Publication year - 2011
Publication title -
proteins: structure, function, and bioinformatics
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.699
H-Index - 191
eISSN - 1097-0134
pISSN - 0887-3585
DOI - 10.1002/prot.23104
Subject(s) - t cell receptor , major histocompatibility complex , molecular dynamics , molecular recognition , computational biology , receptor , biophysics , chemistry , function (biology) , dissociation (chemistry) , molecule , t cell , biology , immune system , microbiology and biotechnology , genetics , biochemistry , computational chemistry , organic chemistry
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.