Potential Explanation of the Mechanism for Loss of Function with G233D Mutation in Platelet Glycoprotein Ib[alpha]: Results fromMolecular Dynamics Simulation

Background: Platelet play crucial role for the onset of acute coronary syndrome. The initial binding following vessel injury is exclusively mediated by the binding of von Willebrand factor (VWF) and platelet glycoprotein (GP) Ib α . Previous biological experiments revealed loss of function of platelet expressing GPIb α with G233D mutation. Objective: To elucidate the mechanism underlining the loss of function in G233D mutant. Methods: Dynamic fluctuating three-dimensional structures and the Potential of Mean Force (PMF) were calculated for the binding of VWF and platelet GPIb α in wild-type or G233D mutant. PMF were calculated at each 0.5Å for 25 Å to 65 Å of mass center distance between GPIb α and VWF. The energy required to dissociate the bond between GPIb α and VWF was calculated by subtracting the lowest PMF from the PMF at 65 Å mass center distance. Chemistry at HARvard Molecular Mechanics (CHARMM) force field with NAnoscale Molecular Dynamics (NAMD) was used for calculation. The initial structure of each mutant was obtained by inducing single amino-acid substitution with Visual Molecular Dynamics (VMD) to the stable water-soluble binding structure of wild-type VWF and GPIb α . Results: The energetically most stable binding structure of VWF and GPIb α in wild-type and G233D did not differ substantially (Figure panel A). However, The energy required to dissociate the bond between GPIb α and VWF was 4.32 kcal/mol (19.5 %) lower for G233D mutant compared to wild-type (Figure panel B). Conclusions: Our results suggest that the reduction of dissociation energy of single molecule of G233D GPIb α mutant as a possible explanation for the reduced platelet adhesion under blood flow condition.