A Mechanism for Localized Dynamics-driven Affinity Regulation of the Binding of von Willebrand Factor to Platelet Glycoprotein Ibα

Binding of the A1 domain of von Willebrand factor (vWF) to glycoprotein Ib alpha (GPIb alpha) results in platelet adhesion, activation, and aggregation that initiates primary hemostasis. Both the elevated shear stress and the mutations associated with type 2B von Willebrand disease enhance the interaction between A1 and GPIb alpha. Through molecular dynamics simulations for wildtype vWF-A1 and its eight gain of function mutants (R543Q, I546V, Delta SS, etc.), we found that the gain of function mutations destabilize the N-terminal arm, increase a clock pendulum-like movement of the alpha 2-helix, and turn a closed A1 conformation into a partially open one favoring binding to GPIb alpha. The residue Arg(578) at the alpha 2-helix behaves as a pivot in the destabilization of the N-terminal arm and a consequent dynamic change of the alpha 2-helix. These results suggest a localized dynamics-driven affinity regulation mechanism for vWF-GPIb alpha interaction. Allosteric drugs controlling this intrinsic protein dynamics may be effective in blocking the GPIb-vWF interaction.