Article ID | Journal | Published Year | Pages | File Type |
---|---|---|---|---|
442916 | Journal of Molecular Graphics and Modelling | 2012 | 10 Pages |
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.
Graphical abstract.Figure optionsDownload full-size imageDownload high-quality image (271 K)Download as PowerPoint slideHighlights► Molecular interactions between VWF A1 domain and GPIbα are investigated. ► Binding is promoted by the long-range electrostatic interactions. ► Final complex formation is maintained by the hydrophobic interactions. ► The hot spots for the initial binding are all charged residues. ► Favorable hydrophobic contribution from M239 is significant for complex formation.