Abstract
The multi-domain protein von Willebrand factor is crucial in the blood coagulation process at high shear. The A1 domain binds to the platelet surface receptor glycoprotein Ibalpha (GpIb alpha) and this interaction is known to be strengthened by tensile force. The molecular mechanism behind this observation was investigated here by molecular dynamics simulations. The results suggest that the proteins unbind through two distinct pathways depending whether a high-tensile force is applied or whether unbinding happens through thermal fluctuations. In the high-force unbinding pathway the A1 domain was observed to rotate away from the C-terminus of GpIb alpha. In contrast, during thermal unbinding the A1 domain rotated in the opposite direction as in the high-force pathway and the distance between the terminii of A1 and the GpIb alpha C-terminus shortened. This shortening was reduced and the lifetime of the bond extended if a moderate tensile force was applied across the complex. This suggests that the thermal unbinding pathway is inhibited by a moderate tensile force which is in agreement with the catch bond property shown previously in single molecule experiments. A designed mutant of GpIb alpha is suggested here in order to test in vitro the thermal unbinding pathway observed in silico.