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

Abstract

High resolution crystal structure of stimulatory peptide-MHC (pMHC) ligands bound to TCR revealed different conformation of the two peptides at positions P6 and V7 compared to the conformation of the same peptides presented by unliganded MHC. Supercomputer simulation and well-tempered metadynamics approach revealed several meta-stable non-canonical TCR-pMHC interactions that depend on the conformation of the MHC-bound peptides. The diversity of meta-stable states was significantly more represented in 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 TCR recognizing pMHC ligand. It appears that TCR 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 non-stimulatory pMHC ligand revealed markedly less meta-stable non-canonical interactions and disengaged from the pMHC. This suggests that productive TCR-mediated signaling may depend on non-canonical interactions between TCR 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.