Structural Mechanism of TCR-pMHC Catch Bonding

T cells perform the remarkable task of determining whether an antigen presenting cell (APC) is healthy or unhealthy by probing only small peptide fragments displayed on the APC’s surface. Recent experiments have found that T cell receptors (TCRs) form catch-slipbonds with some peptides displayed by pMHC ligands, but slip bonds with other peptides. These experiments suggest that T cells may utilize the catch-slip behaviors of TCR-pMHC to achieve high fidelity peptide discrimination by applying (pN scale) forces to TCR-pMHC bonds. Recent studies have made significant progress in elucidating the mechanism of TCR-pMHC catch-slip bonding, but a physical model is still lacking. We have developed a mathematical framework of protein-ligand binding under force, showing how catch bonding is induced by singularities in the “flow field” that describes force-induced molecular deformations. By applying this mathematical framework to a free energy landscape model of TCR-pMHC, we show how minor changes in the peptide binding interaction convert the bond between slip and catch-slip behaviors.