bioRxiv2019
Cellular structures are continually subjected to forces, which may serve as mechanical signals for cells through their effects on biomolecule interaction kinetics. Typically, molecular complexes interact via \"slip bonds,\" so applied forces accelerate off rates by reducing transition energy barriers. However, biomolecules with multiple dissociation pathways may have considerably more complicated force dependencies. This is the case for DNA-binding proteins that undergo \"facilitated dissociation,\" in which competitor biomolecules from solution enhance molecular dissociation in a concentration-dependent manner. Using simulations and theory, we develop a generic model that shows that proteins undergoing facilitated dissociation can form an alternative type of molecular bond, known as a \"catch bond,\" for which applied forces suppress protein dissociation. This occurs because the binding by protein competitors responsible for the facilitated dissociation pathway can be inhibited by applied forces. Within the model, we explore how the force dependence of dissociation is regulated by intrinsic factors, including molecular sensitivity to force and binding geometry, and the extrinsic factor of competitor protein concentration. We find that catch bonds generically emerge when the force dependence of the facilitated unbinding pathway is stronger than that of the spontaneous unbinding pathway. The sharpness of the transition between slip- and catch-bond kinetics depends on the degree to which the protein bends its DNA substrate. These force-dependent kinetics are broadly regulated by the concentration of competitor biomolecules in solution. Thus, the observed catch bond is mechanistically distinct from other known physiological catch bonds because it requires an extrinsic factor - competitor proteins - rather than a specific intrinsic molecular structure. We hypothesize that this mechanism for regulating force-dependent protein dissociation may be used by cells to modulate protein exchange, regulate transcription, and facilitate diffusive search processes.\n\nStatement of significanceMechanotransduction regulates chromatin structure and gene transcription. Forces may be transduced via biomolecular interaction kinetics, particularly, how molecular complexes dissociate under stress. Typically, molecules form \"slip bonds\" that dissociate more rapidly under tension, but some form \"catch bonds\" that dissociate more slowly under tension due to their internal structure. We develop a model for a distinct type of catch bond that emerges via an extrinsic factor: protein concentration in solution. Underlying this extrinsic catch bond is \"facilitated dissociation,\" whereby competing proteins from solution accelerate protein-DNA unbinding by invading the DNA binding site. Forces may suppress invasion, inhibiting dissociation, as for catch bonds. Force-dependent facilitated dissociation can thus govern the kinetics of proteins sensitive to local DNA conformation and mechanical state.