Shear-induced rotation mechanism of VWF A2 domain plays important role in mediating platelet adhesion

Abstract

von Willebrand Factor (VWF) is a blood glycoprotein which plays an important role in mediating platelet adhesion to damaged blood vessel during hemostasis. It is known that the shear stress in blood stretches the A2 structural domain and regulates the platelet adhesion behavior through the cleavage by the metalloprotease ADAMTS13. The mechanical forces mediating the cleavage rate and the unfolding mechanism of A2 domain where the cleavage site (Tyr1605–Met1606 in β₄) resides is highly related to proper regulation of VWF proteolysis for maintaining normal hemostasis. Past studies have addressed the unfolding mechanism by conducting AFM experiments or SMD simulations. However, the local interaction of VWF with the surrounding fluid under shear flow were not considered, which might influence the unfolding pathway and the force required to facilitate the exposure of the cleavage site. Therefore, it's intriguing to study the unfolding pathway under shear flow at the molecular level to identify the conformational intermediates and force responses. In this study, we perform a molecular dynamics simulation with imposed shear flow on the VWF A2 domain to reveal how shear flow alters its molecular structure. Our results reveal that the loading condition strongly affects the molecular unfolding of VWF on its capability of rotation, which is crucial for stabilizing the βsheet and reducing the unfolding force under physiological condition. These findings provide fundamental knowledge for the development of future treatments of related diseases.