Molecular Dynamics Simulation On The Interactions Between Von Willebrand Factor And GPIbα

Thrombosis is associated with serious diseases, such as stroke and acutemyocardial infarction, which are harmful to human health. Arterial thrombusformation is a complicated process regulated by many factors and it is considered tohave three important stages, including initial platelet adhesion to sites of vascularinjury, firm platelet adhesion and platelet aggregation. However, the microscopicinformation about arterial thrombus formation and its regulation are far from adequate.Therefore, all-atom models and molecular dynamics (MD) simulations coupled withmolecular mechanics-Poisson-Boltzmann surface area method (MM-PBSA) are usedin the present study to investigate the binding between von Willebrand factor (VWF)and its platelet surface receptor glycoprotein Ibα (GPIbα), providing the molecularbasis of the driving forces and the molecular mechnisms of initial platelet adhesion inarterial thrombus formation.First, the all-atom models of VWF A1domain and GPIbα are constructed. Then,MD simulations are performed to investigate the molecular interactions betweenVWF A1domain and GPIbα in complex, and the binding dynamics in both water andphysiological saline. Moreover, the microscopic details and the hot spots areidentified through MM-PBSA free energy decomposition analysis.Faster binding is observed in water than that in physiological saline in thebinding dynamics, and patches of opposite charges are observed at the bindinginterface as indicated in the electrostatic surface potentials analysis. Therefore, theelectrostatic interactions are proposed to be important driving forces for promotingthe binding. Moreover, the free energy decomposition results indicate that the bindingis promoted by the long-range electrostatic interactions and then maintained byhydrophobic interactions. Free energy decomposition and pair interaction analysisindicate that the residues E14, E128, D175, D83, E151, D106, D63, E5, D18, E225,D235in GPIbα, and K608, K569, K644, R571, K572, R636, K599in VWF A1domain are hot spots for the initial binding. For the final complex formation,72%ofthe favorable contributions are from hydrophobic interactions. The residues F199,M239, Y600and F603are critical for final complex formation.The molecular interactions between VWF A1domain and GPIbα are examinedin the present study. Therefore, the driving forces for the initial platelet adhesion in arterial thrombosis and its regulation have been demonstrated. The molecularmechanisms of the initial platelet adhesion would be helpful for the development ofnovel and more potent antithrombotic agents.