Using molecular dynamics simulations to interrogate T cell receptor non-equilibrium kinetics

[Display omitted] •Insights into the atomic-scale interaction of the T Cell Receptor with the peptide Major Histocompatibility Complex.•Investigation of the physiochemical features that correspond with T Cell Receptor recognition during dynamic dissociation.•Implications of force-dependent non-equilibrium kinetics on T Cell Receptor mechanosensing. An atomic-scale mechanism of T Cell Receptor (TCR) mechanosensing of peptides in the binding groove of the peptide-major histocompatibility complex (pMHC) may inform the design of novel TCRs for immunotherapies. Using steered molecular dynamics simulations, our study demonstrates that mutations to peptides in the binding groove of the pMHC – which are known to discretely alter the T cell response to an antigen – alter the MHC conformation at equilibrium. This subsequently impacts the overall strength (duration and length) of the TCR-pMHC bond under constant load. Moreover, physiochemical features of the TCR-pMHC dynamic bond strength, such as hydrogen bonds and Lennard-Jones contacts, correlate with the immunogenic response elicited by the specific peptide in the MHC groove. Thus, formation of transient TCR-pMHC bonds is characteristic of immunogenic peptides, and steered molecular dynamics simulations can be used in the overall design strategy of TCRs for immunotherapies.