T-Cell Receptor Binding Affects the Dynamics of the Peptide/MHC-I Complex

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 dose, while the presence of the T-cell receptor inhibits these breathing-like motions.