The catch bond mechanism between von Willebrand factor and platelet surface receptors investigated by molecular dynamics simulations

Abstract

The multi-domain protein von Willebrand Factor is crucial in the blood coagulation process at high shear. The A1 domain binds to the platelet surface receptor glycoprotein Ibα (GpIbα) and this interaction is known to be strengthened by tensile force. The molecular mechanism behind this observation was investigated here by molecular dynamics simulations. The results suggest that the proteins unbind through two distinct pathways depending whether a high tensile force is applied or whether unbinding happens through thermal fluctuations. In the high force unbinding pathway the A1 domain was observed to rotate away from the C-terminus of GpIbα. In contrast, during thermal unbinding the A1 domain rotated in the opposite direction as in the high force pathway and the distance between the terminii of A1 and the GpIbα C-terminus shortened. This shortening was reduced and the lifetime of the bond extended if a moderate tensile force was applied across the complex. This suggests that the thermal unbinding pathway is inhibited by a moderate tensile force which is in agreement with the catch bond property shown previously in single molecule experiments. A designed mutant of GpIbα is suggested here in order to test in vitro the thermal unbinding pathway observed in silico.

Role of Electrostatic Interactions in Binding of Thrombin to the Fibrinogen γ′ Chain

“…A similar strategy is employed in the catch-bonds between platelet glycoprotein Ib and von Willebrand factor, and allows rapidly-moving platelets to be slowed down by sequential tethering events to von Willebrand factor coated on injured subendothelium. 23 The γ′ chain/thrombin exosite II interaction by itself would result in both a rapid association and a rapid dissociation. However, during blood coagulation, thrombin also interacts with intact fibrin through exosite I.…”

Tight Conformational Coupling between the Domains of the Enterotoxigenic Escherichia coli Fimbrial Adhesin CfaE Regulates Binding State Transition

“…The proteins were aligned with the longest dimension parallel to the x axis and solvated in a rectangular water box (135 ϫ 80 ϫ 80 Å 3 ) containing 150 mM NaCl, resulting in a system with a total of ϳ80,000 atoms. Standard protocols for the non-bonded interactions, temperature, and pressure were described previously (26). For each of the proteins, three 10-ns-long simulations were performed at 27°C to equilibrate their structures.…”

Advances in Experiments and Modeling in Micro- and Nano-Biomechanics: A Mini Review

“…59 But for vWF-A1/GPIba complex, MDS exhibits its conformational flexibility and the stabilizing electrostatic interactions between these two proteins. 40 The unfolding of the central b-sheet of vWF-A2 is proposed to start from its edges and then propagate into its center. 13 The allostery of P-selectin lectin (Lec) domain followed by an epithelial growth factor (EGF)-like domain is recently visualized using free MDS.…”

“…55 SMD simulations on unbinding of receptor from its ligand, such as P-selectin glycoprotein ligand 1 (PSGL-1) from P-selectin and glycoprotein Iba (GPIba) from vWF-A1, have provided insights into the molecular mechanism underlying catch-bond. 32,40,58,103 Flow MDS was inspired from FC assay and first carried out by Lou and Zhu 59 and further improved by Chen et al…”