WFU Physics Colloquium

TITLE: Protein Optimization and Biophysical Requirements for Hemostasis Initiation

SPEAKER: Professor Nathan E. Hudson,

TIME: Wednesday February 8, 2017 at 4:00 PM

PLACE: Room 101 Olin Physical Laboratory

Blood clotting stops flow at the site of vascular injury (i.e., bleeding). To seal a wound, the proteins involved in clotting must form and sustain bonds with blood cells and the walls of blood vessels in spite of the pulsing flow produced by the beating heart. This talk will feature the protein von Willebrand Factor (VWF) and will demonstrate how the VWF’s mechanical properties determine the initiation and fate of blood clots.

VWF adheres to platelets via binding of its A1 domain to the platelet surface receptor GPIbα. Using single molecule techniques, we probed the force-dependent binding frequency (on-rate) and dissociation frequency (off-rate) of the VWF A1 domain with GPIbα We find that force can switch A1 or GPIbα into a state with a faster on-rate and slower off-rate, which we hypothesize, enhances blood clot formation. In von Willebrand disease, the most commonly inherited bleeding disorder, the mechanical properties are altered by mutations in A1 and/or GPIbα We find that these mutations have little difference in on-rate and off-rate at zero force, but when the bond is subjected to a force of 15pN, there is a ~200-fold difference in bond kinetics. Using polymer theory to derive an effective single molecule concentration, we show that our zero-force results agree with previous measurements of A1-GPIbα binding performed in bulk. VWF is an excellent example of the physical optimization of mechanical proteins. Insights we gain from biophysical studies of such molecules can be incorporated into the design strategies of novel materials and provide innovative targets for next-generation therapeutics.