Dynamic mechanism for the ligand discrimination by αβ T-cell receptor enhanced by mechanical load.

TheαβT-Cell Receptor (TCR) enhances recognition of its cognate peptide-bound major histocompatibility complex (pMHC) molecule by activating a catch bond under physiological piconewton-level force. Our recent molecular dynamics (MD) simulations on the JM22 TCR suggest that catch bond activation involves suppressing intra-domain motion by the applied force, thereby stabilizing the TCR-pMHC interface. To further investigate the role of mechanical load in peptide discrimination, we performed all-atom MD simulations of the A6 and B7 TCRs, which share the same TCRβ and bind to the same HLA-A2/Tax pMHC (PDB 1AO7 and 1BD2). For both TCRs, we found that the overall fit of the TCRαβ-pMHC complex was enhanced by applied load in the 19-pN range. High load stabilized contacts between the pMHC and the TCR as well as between TCR subdomains. The two TCRs employed a similar strategy where theα chain was modified more by load compared to the β chain. To assess whether this load-dependent behavior is unique to agonist peptides, we additionally studied A6 TCR bound to peptides bearing point mutations to Tax (PDB 3QFJ, 1QSE, 1QRN, and 1QSF). The TCR in these complexes are structurally very similar in static x-ray structures, yet the mutations lead to differences in T-cell response. For weak agonists, force temporarily maintained TCR-pMHC and TCR contacts, yet the interface exhibited destabilization within the 1-µs simulation time. For antagonists, the applied load did not stabilize TCR domain motion, which was related to significant losses in TCR-pMHC interface contacts. Our simulations reveal an avenue by which the force-based catch bond mechanism selectively works with the cognate peptide antigen.