The catch bond mechanism between von Willebrand factor and platelet surface receptors investigated by molecular dynamics simulations.
The catch bond mechanism between von Willebrand factor and platelet surface receptors investigated by molecular dynamics simulations.
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DOI：
10.1002/prot.22759
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发表时间：
2010-08-15
期刊：
影响因子：
2.9
通讯作者：
Thomas W
中科院分区：
文献类型：
--
作者：
Interlandi G;Thomas W
多结构域蛋白血管性血友病因子在高剪切下的血液凝固过程中至关重要。A1结构域与血小板表面受体糖蛋白Ibα（GpIbα）结合，已知这种相互作用可通过张力加强。本文通过分子动力学模拟研究了这一现象背后的分子机制。结果表明，蛋白质通过两种不同的途径解结合，这取决于是否施加高张力或解结合是否通过热波动发生。在强力解结合途径中，观察到A1结构域旋转远离GpIbα的C-末端。与此相反，在热解结合过程中，A1结构域在相反的方向旋转，在高的力的途径和A1的末端和GpIbα C-末端之间的距离缩短。如果在复合物上施加适度的张力，这种缩短会减少，粘合的寿命会延长。这表明，热解结合途径被抑制由一个温和的张力，这是在协议与捕获键的性能在单分子实验中先前显示。本文提出了一种设计的GpIbα突变体，以在体外测试在计算机上观察到的热解结合途径。
The multi-domain protein von Willebrand Factor is crucial in the blood coagulation process at high shear. The A1 domain binds to the platelet surface receptor glycoprotein Ibα (GpIbα) and this interaction is known to be strengthened by tensile force. The molecular mechanism behind this observation was investigated here by molecular dynamics simulations. The results suggest that the proteins unbind through two distinct pathways depending whether a high tensile force is applied or whether unbinding happens through thermal fluctuations. In the high force unbinding pathway the A1 domain was observed to rotate away from the C-terminus of GpIbα. In contrast, during thermal unbinding the A1 domain rotated in the opposite direction as in the high force pathway and the distance between the terminii of A1 and the GpIbα C-terminus shortened. This shortening was reduced and the lifetime of the bond extended if a moderate tensile force was applied across the complex. This suggests that the thermal unbinding pathway is inhibited by a moderate tensile force which is in agreement with the catch bond property shown previously in single molecule experiments. A designed mutant of GpIbα is suggested here in order to test in vitro the thermal unbinding pathway observed in silico.
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DOI：
10.1083/jcb.200810002
发表时间：
2009-06-29
期刊：
The Journal of cell biology
影响因子：
--
作者：
Kong F;García AJ;Mould AP;Humphries MJ;Zhu C
通讯作者：
Zhu C
影响因子：
4.8
作者：
Emsley, J;Cruz, M;Liddington, R
通讯作者：
Liddington, R
影响因子：
5.7
作者：
Fukuda, K;Doggett, TA;Liddington, RC
通讯作者：
Liddington, RC
影响因子：
2.4
作者：
Chen, JM;López, KA
通讯作者：
López, KA
影响因子：
2.9
作者：
Interlandi, Gianluca
通讯作者：
Interlandi, Gianluca