ИСТИНА

The leading cause of morbidity and mortality in developed countries are complications, caused by atherothrombosis - infarctions and strokes. Recent research showed that blood protein called von Willebrand factor plays a key role in the formation of arterial thrombus under extreme hydrodynamic conditions associated with vessel stenosis. However, the exact mechanism responsible for the formation of occlusive thrombus is currently unknown. It was suggested that flow-induced unfolding of von Willebrand factor observed in vitro under high shear conditions might be responsible for the formation of pathological thrombus in patients. Von Willebrand factor is a huge multimeric protein built up of the crosslinked dimers. It is believed that physiologically relevant are multimers having over 20 dimers. Each dimer consists of several domains, including two flow-sensitive A2-domains, which are capable of unfolding under external forces. The classical model of von Willebrand factor describes the molecule as a chain of linked spheres with equal radiuses R which correspond to one dimer of the protein. This coarse model allows to analyze the conformational dynamics of the protein during physiologically relevant time scales. However, classical model does not account for the possibility of A2-domain unfolding which might seriously influence on the conformational dynamics of the molecule. The main objective of this work was to elucidate the impact of A2 domains unfolding on the conformational dynamics of the molecule under various hydrodynamic conditions in silico. To do that, the existing classical model of von Willebrand factor was modified to account for the unfolding and refolding of flow-sensitive A2-domains. In order to compare the new model with classical one we performed massive computations of von Willebrand factor’s dynamics under various hydrodynamic conditions for both models. The results of our simulations show that A2 unfolding might influence the conformational dynamics of protein multimers, increasing their unfolding probability under both shear and elongational flows. Our results show that A2 domain unfolding of von Willebrand factor might impact the conformational dynamics of the protein multimers under a physiologically extreme hydrodynamic conditions, corresponding to those expected in stenosed arteries.