Abstract
The recognition of peptide/MHC by T-cell receptors is one of the most important interactions in the adaptive immune system. A large number of computational studies have investigated the structural dynamics of this interaction. However, to date only limited attention has been paid to differences between the dynamics of peptide/MHC with the T-cell receptor bound and unbound. Here we present the first large-scale molecular dynamics simulation study of this type investigating HLA-B*08:01 in complex with the Epstein-Barr virus peptide FLRGRAYGL and all possible single-point mutations (n = 172). All of the simulations were performed with and without the LC 13 T-cell receptor for a simulation time of 100 ns, yielding 344 simulations and a total simulation time of 34 400 ns. Our study is 2 orders of magnitude larger than the average T-cell receptor/peptide/MHC molecular dynamics simulation study. This data set provides reliable insights into alterations of the peptide/MHC-I dynamics caused by the presence of the T-cell receptor. We found that simulations in the presence of T-cell receptors have more hydrogen bonds between the peptide and MHC, altered flexibility patterns in the MHC helices and the peptide, a lower MHC groove width range, and altered solvent-accessible surface areas. This indicates that without a T-cell receptor the MHC binding groove can open and close, while the presence of the T-cell receptor inhibits these breathing-like motions.
Highlights
The interaction between T-cell receptors (TCRs) and protein fragments presented by major histocompatibility complexes (MHCs)/β2 microglobulin (β2M) is one of the most important events in the adaptive immune system.[1]
The involvement of structural dynamics in TCR triggering is supported by several lines of evidence: (i) a mechanical pushing or pulling force on the TCR is inevitable during pMHC binding and unbinding;[6] (ii) CD3 is relatively rigid, and the FG loop of the TCR constant β-domain is in direct contact with the membrane-distal end of CD3,7 so mechanical forces acting on the TCR could be directly transmitted into the cell; (iii) T-cell activation is optimal if the pMHC is anchored to an artificial surface;[8] (iv) elongation of the pMHC ectodomain reduces TCR triggering[9] because only a reduced mechanical force acts on the TCR; (v) mechanical forces on the TCR enhance TCR triggering.[10]
We show the simulation of the wild-type peptide FLRGRAYGL bound by HLA-B*08:01 with the LC13 TCR
Summary
The interaction between T-cell receptors (TCRs) and protein fragments (called peptides or antigens) presented by major histocompatibility complexes (MHCs)/β2 microglobulin (β2M) is one of the most important events in the adaptive immune system.[1] Intracellular proteins are degraded by proteasomes into peptides. These peptides are transported into the endoplasmic reticulum (ER) and bound inside the binding groove of MHC complexes. The peptide/MHC complexes are presented on the surface of the cell, where they can be recognized by the TCRs of T-cells. The involvement of structural dynamics in TCR triggering is supported by several lines of evidence (reviewed in ref 2): (i) a mechanical pushing or pulling force on the TCR is inevitable during pMHC binding and unbinding;[6] (ii) CD3 is relatively rigid, and the FG loop of the TCR constant β-domain is in direct contact with the membrane-distal end of CD3,7 so mechanical forces acting on the TCR could be directly transmitted into the cell; (iii) T-cell activation is optimal if the pMHC is anchored to an artificial surface;[8] (iv) elongation of the pMHC ectodomain reduces TCR triggering[9] because only a reduced mechanical force acts on the TCR; (v) mechanical forces on the TCR enhance TCR triggering.[10]
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