Dynamic conformational response of von Willebrand factor to varying shear stress: A hybrid computational approach

• Pioneering a hybrid computational approach to study vWF dynamics under shear flow. • Detailed analysis of the conformational behavior of A1, A2, A3, and D’D3 domains in varying shear stresses. • Demonstrating significant domain elongation and compaction, especially in A2 and A3 domains, under conditions mimicking arterial stenosis. • Exploring how random forces influence vWF configurations and interactions with platelets in blood flow. • Providing new insights into vWF’s mechanistic role in clotting and its potential in pathological scenarios. This computational study examines the mechanobiological responses of von Willebrand Factor (vWF) to different shear stress levels, emphasizing the unique structural dynamics of its various domains. We introduce a novel coarse-grained model, representing each cluster of six amino acids as a bead, to synthesize the Lattice Boltzmann method with Brownian dynamics. This approach captures the vWF molecule’s conformational adaptability across a spectrum of shear rates, ranging from 5 to 5e + 7s −1 , encompassing normal physiological flows to those resembling the high-shear environment of arterial stenosis. Our results reveal domain-specific responses of vWF, particularly in the A2 and A3 domains, which demonstrate significant elongation under elevated shear—reflecting their pivotal roles in clotting processes. Moreover, the study underscores the critical influence of random thermal forces on the molecule’s conformation, with simulations including these forces showing substantially greater conformational variability compared to those without. As shear rates increase, we observe a notable reorganization in the spatial arrangement of vWF domains. This reconfiguration is most evident in the increased separation between the A1 and D’D3 domains under high shear conditions, potentially enhancing the accessibility of platelets to key binding sites on vWF. These findings are paramount for a deeper understanding of vWF’s mechanical behavior in blood clotting and thrombosis, particularly the delicate balance between facilitating platelet adhesion and avoiding excessive stretching that could lead to thrombosis. Our work provides a foundation for future studies investigating vWF behavior in complex flow geometries and its interactions with other blood components. Such insights pave the way for more informed therapeutic strategies targeting vWF function in vascular health and disease, potentially leading to improved treatments for thrombotic disorders.