Dynamics of type IIb mutation-induced conformational changes in the von Willebrand factor A1 domain

Von Willebrand factor (vWF) is the largest soluble protein in human blood. In regions of high shear rates such as those encountered in stenosed arteries vWF binds platelet GpIb and induces platelet activation. This phenomenon is manifested in pathological conditions such as cerebral ischemia and myocardial infarction. While wild-type vWF does not bind GpIb under static conditions, in Type IIb von Willebrand disease (vWD) vWF shows a constitutive affinity for GpIb. In this study, molecular dynamics simulations were performed to generate the structure of the Type IIb mutant Ile 546 Val (I546V). The equilibrium structure of the I546V mutant obtained here is in qualitative agreement with the experimentally determined crystal structure for this mutant. Our results demonstrate that the single amino-acid substitution at the bottom of the vWF structure causes a rapid rearrangement of the salt bridge network in the vWF A1 domain that results in a re-orientation of the functional group of Asp 560, 27Å from the site of the mutation. This residue has been previously shown to be involved in GpIb binding. These results provide dynamic information on the changes within the vWF A1 domain that regulate vWF function. These features may be relevant to our understanding of the mechanism of shear-induced platelet activation.