(661h) Molecular Dynamics Simulation On the First Stage of Thrombus Formation

Molecular interaction between the protein von Willebrand factor (VWF) A1 domain and its platelet surface receptor glycoprotein Ibα (GPIbα) promotes the initial adhesion of platelets to the sites of vascular injury, which intiates thrombus formation. So, this molecular interaction is crucial in the thrombus formation. However, little is understood about this interaction at molecular level, and it is very difficult to investigate the details by experiments. In this work, all-atom models and molecular dynamics simulation are used to investigate the interactions between VWF A1 domain and GPIbα, and to examine the disassociation/binding processes. Two solution conditions, water and physiological saline are considered. In the simulations, faster binding of VWF A1 domain and GPIbα is observed in water than that in physiological saline, and larger electrostatic interaction than hydrophobic interaction is also observed in the binding process. Then, electrostatics analysis is performed using Adaptive Poisson-Boltzmann Solver (APBS) to examine the electrostatic surface potentials of VWF A1 domain and GPIbα. Oppositely charged regions are observed at the interface between VWF A1 domain and GPIbα. Moreover, the interaction free energy is analyzed in details using molecular mechanics-Poisson-Boltzmann surface area (MM-PBSA) approach. It is shown that the binding process is first driven by electrostatic interaction and then stabilized by hydrophobic interaction. The results indicate that electrostatic interaction is dominate for the complex formation of VWF A1 domain and GPIbα. This has provided the molecular insight into the initial adhesion of platelets.