Topology of molecular deformations induces triphasic catch bonding in selectin–ligand bonds

Abstract

Among the long-standing efforts to elucidate the physical mechanisms of protein–ligand catch bonding, particular attention has been directed at the family of selectin proteins. Selectins exhibit slip, catch–slip, and slip–catch–slip bonding, with minor structural modifications causing major changes in selectins’ response to force. How can a single structural mechanism allow interconversion between these various behaviors? We present a unifying theory of selectin–ligand catch bonding, using a structurally motivated free energy landscape to show how the topology of force-induced deformations of the molecular system produces the full range of observed behaviors. We find that the pathway of bond rupture deforms in non-trivial ways, such that unbinding dynamics depend sensitively on force. This implies a severe breakdown of Bell’s theory—a paradigmatic theory used widely in catch bond modeling—raising questions about the suitability of Bell’s theory in modeling other catch bonds. Our approach can be applied broadly to other protein–ligand systems.