Paper Citing NAMD - Abstract
Huang, Qingsheng; Lou, Jizhong; Wu, Jianhua; Zhu, Cheng
Conformational Transition of Glycoprotein Ib alpha Mutants in Flow Molecular Dynamics Simulation
CELLULAR AND MOLECULAR BIOENGINEERING, 4:495-504, SEP 2011
Glycoprotein Ib alpha (GPIb alpha) 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 beta-switch region of GPIb alpha N can be regulated by flow. Flow induces a loop-to-beta-hairpin conformational change in this region, which is a suggested mechanism for the flow-enhanced binding of GPIb alpha 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 beta-switch. The results demonstrate that the gain-of-function mutations G233V, D235V, and K237V promote the conformational transition toward beta-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 beta-hairpin, and also by the decreased flexibility of one strand of the beta-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.
