The role of peptide conformation presented by MHC in the induction of TCR triggering

A high-resolution crystal structure of stimulatory peptide-major histocompatibility complex (pMHC) ligands bound to T cell receptor (TCR) revealed different conformations of the two peptides at positions P6 and V7 compared to the conformation of the same peptides presented by unliganded MHC. Supercomputer simulations and a well-tempered metadynamics approach revealed several metastable noncanonical TCR-pMHC interactions that depend on the conformation of the MHC-bound peptides. The diversity of metastable states was significantly more represented in the signaling TCR-pMHC complex. These findings suggest that TCR-pMHC recognition can be informed by a conformation of peptide presented by MHC that notably influences the orientation of a TCR-recognizing pMHC ligand. It appears that TCRs bound to stimulatory pMHC possess a significantly higher degree of freedom to assume various metastable TCR orientations, which are distinct from canonical docking. In contrast, TCR interacting with nonstimulatory pMHC ligand revealed markedly less metastable noncanonical interactions and disengaged from the pMHC. This suggests that productive TCR-mediated signaling may depend on noncanonical interactions between TCRs and pMHC, either facilitating early recognition events or providing new contacts for catch-bond formation. Our discovery can inform future attempts to simulate the catch-bond formation mechanism in TCR-pMHC recognition, allowing the formation of new bonds mediating alternative peptide presentation.