Conformational Transition of Glycoprotein Ibα Mutants in Flow Molecular Dynamics Simulation

Abstract

Glycoprotein Ibα (GPIbα) interacts with von Willebrand factor (VWF) inducing the tethering of platelets to injured vessel walls and subsequent hemostasis process. We have previously shown that the conformation of the β-switch region of GPIbαN can be regulated by flow. Flow induces a loop-to-β-hairpin conformational change in this region, which is a suggested mechanism for the flow-enhanced binding of GPIbα to VWF-A1. To further evaluate the mechanism and obtain more complete evidences, here we performed flow molecular dynamics simulations of wild type and a number of mutants of the β-switch. The results demonstrate that the gain-of-function mutations G233V, D235V, and K237V promote the conformational transition toward β-hairpin, while the loss-of-function mutation Q232V impedes the transition. The promotion is caused mainly by the improved polarity similarity of the paired residues on the β-hairpin, and also by the decreased flexibility of one strand of the β-switch. The gain-of-function mutations exert the influence locally, affecting only hydrogen bonds near the mutated residues. The impediment of the loss-of-function mutant may be non-essential hydrophobic interactions blocking the conformational change.