T Cell Receptor Non-Equilibrium Kinetics

ABSTRACT An atomic-scale mechanism describing the role of mechanosensing in T Cell Receptor (TCR) recognition 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 dynamic 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 – influence MHC conformation and thus the overall strength of the TCR-pMHC bond including duration and length 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 a characteristic of immunogenic peptides and is mediated by stabilized interactions.x