TCB Publications - Abstract

Xueqing Zou, Yanxin Liu, Zhongzhou Chen, Gloria Ines Cárdenas-Jirón, and Klaus Schulten. Flow-induced β-hairpin folding of the glycoprotein Ibα β-switch. Biophysical Journal, 99:1182-1191, 2010. (PMC: 2920744)

ZOU2010 Mechanical force affects the structural and mechanical properties of proteins as elucidated in many single molecule experiments and steered molecular dynamics simulations. Recently, flow induced shear has been identified as a regulatory driving force in blood clotting. Shear induces a loop $\rightarrow$ $\beta$-hairpin transition of the glycoprotein Ib$\alpha$ (GPIb$\alpha$) $\beta$-switch which increases the affinity for binding to the von Willebrand factor, a key step in blood clot formation and wound healing. Here, we investigate through altogether 1.6 $\mu$s molecular dynamics simulations the mechanism underlying the flow-induced loop $\rightarrow$ $\beta$-hairpin transition. Simulations sample for different flow velocities the key steps involved in the loop $\rightarrow$ $\beta$-hairpin transition, namely, dihedral rotation and side-group packing. Adaptive biasing force simulations are employed to determine the energy required for extending the $\beta$-switch from its loop to its hairpin state. Flow is found to lower the energy barrier between loop and $\beta$-hairpin state permitting the transition to occur spontaneously for fast enough flow. The role of entropy in controlling the loop $\rightarrow$ beta-hairpin transition is illustrated through basic polymer theory.

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