title: Molecular basis of the initial platelet adhesion in arterial thrombosis: molecular dynamics simulations.
abstract: Molecular interactions between the von Willebrand factor (VWF) A1 domain and glycoprotein Ibα (GPIbα) promote the initial adhesion of platelets and subsequent arterial thrombus formation. However, little is understood about the interactions at a molecular level. Therefore, the binding dynamics and involved molecular interactions between VWF A1 domain and GPIbα in both water and physiological saline are investigated using molecular dynamics simulations and all-atom models. Faster binding is observed in water than that in physiological saline, and patches of opposite charges are observed at the binding interface. Moreover, molecular mechanics-Poisson-Boltzmann surface area analysis indicates that the binding is promoted by the long-range electrostatic interactions and then maintained by hydrophobic interactions. For the initial binding, the hot spots include the residues E14, E128, D175, D83, E151, D106, D63, E5, D18, E225, D235 in GPIbα, and K608, K569, K644, R571, K572, R636, K599 in VWF A1 domain. For the final complex formation, however, 72% of the favorable contributions are from hydrophobic interactions. The results provided molecular insight into the initial platelet adhesion. The hot spots identified would be beneficial for developing novel drugs for thrombotic diseases.
authors.affiliation: Department of Biochemical Engineering and Key Laboratory of Systems Bioengineering of the Ministry of Education, School of Chemical Engineering and Technology, Tianjin University, Tianjin 300072, China.
authors.forename: Jian
authors.initials: J
authors.lastname: Li
authors.forename: Lin
authors.initials: L
authors.lastname: Zhang
authors.forename: Yan
authors.initials: Y
authors.lastname: Sun
mesh_terms: D000818:Animals; D006801:Humans; D056004:Molecular Dynamics Simulation; D010973:Platelet Adhesiveness / Q000502:physiology*; D019038:Platelet Glycoprotein GPIb-IX Complex / Q000737:chemistry / Q000378:metabolism; D011485:Protein Binding; D017433:Protein Structure, Secondary; D017434:Protein Structure, Tertiary; D013927:Thrombosis / Q000378:metabolism*; D014652:Vascular Diseases / Q000378:metabolism*; D014841:von Willebrand Factor / Q000737:chemistry / Q000378:metabolism
chemical_list: D019038:Platelet Glycoprotein GPIb-IX Complex; D014841:von Willebrand Factor