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Интеллектуальная Система Тематического Исследования НАукометрических данных |
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Thrombosis in arteries and arterioles relies on platelet aggregation at a site of vascular injury. This process is mediated by a multimeric plasma protein - von Willebrand factor (VWF). It mediates platelet adhesion to injury in a blood flow and responds to hydrodynamic stresses by multiple hierarchical conformational changes that affect its size, stability, and biological functions. VWF multimers respond to hydrodynamic stresses by multiple hierarchical conformational changes that affect its size, stability, and biological functions. Deficiency or abnormal functioning of this protein causes an inherited bleeding syndrome, known as von Willebrand disease. Prior studies revealed that mechanical properties of VWF multimers, their ability to adhere to injury and to bind platelets are strongly related to multiple pH-dependent interactions between globular domains within dimeric subunits. In present work, we develop a multiscale framework for numerical investigation of the relation between hemodynamic conditions and biophysical properties of this protein. A coarse-grained 3D computer model of VWF has been proposed and parameterized to give a good agreement with experimental data. The model is based on the fluctuating Lattice Boltzmann method for modelling the hydrodynamics in the simulation box and the Lagrangian particle dynamics coupled to the fluid by a viscous drag force. We resolve the dynamics of VWF multimers at a subdimer level and to show that VWF’s radius of gyration and its sensitivity to hydrodynamics strongly depend on the interdomain forces. The simulations suggest that the attraction forces between globular domains within the VWF dimer increase its resistance to deformation in a shear flow. We also study the adhesive interactions between VWF and platelets, as well as its shear-dependent proteolysis by ADAMTS13. It is hypothesized that the detailed subdimer dynamics of VWF multimers may be one of the biophysical regulators of initial hemostasis and arterial thrombosis. The results would hopefully help in understanding of shear-induced activation of VWF and give a deeper insight into its role in arterial thrombosis and hemostasis.