内皮素-1 在均匀流中构象改变的分子动力学模拟

内皮素ET-1(Endothelin-1)与其受体ETA(Endothelin-A)和ETB(Endothelin-B)的相互作用控制血管紧张度,维持血压,与心血管疾病关系密切。ET-1与血管内皮的ETB结合介导血管舒张,而与血管平滑肌的ETA和ETB结合则引起血管收缩。ET-1只有在存在正常血流的体内实验才表现出明显的舒张活性,且其结构具有柔性,故推测血流的剪切应力可能控制了它的构象,进而调控它与ETB的结合。文章利用流动分子动力学计算机模拟方法,研究了均匀流中质心受约束的内皮素ET-1的构象。实验结果观察到该分子的羧基端往氨基端靠近,整个分子变得紧凑。这个发现对研究ET-1与ETB的相互作用和设计基于ET-1的心血管药物将会有一定的指导意义。

Molecular Dynamics Simulation of Endothelin-1 Conformational Changes within Uniform Flow

Interactions of ET-1 (Endothelin-1) with its receptors ETA (Endothelin-A) and ETB (Endothelin-B) regulate the vascular tone, maintain the blood pressure, and are closely related to cardiovascular diseases. Binding of ET-1 with ETB in the vascular endothelium induces vasodilation, while binding with ETA and ETB in vascular smooth muscle results in vasoconstriction. Because ET-1 only induces vasodilation in vivo when the blood flow is present, we speculate that the shear stress of the blood flow may control the conformation of ET-1 through its structural flexibility, thus regulate its binding with ETB. By flow molecular dynamics simulation, the conformational changes of ET-1 in uniform flow were studied with its center of mass constrained. It is found that the C-terminal of ET-1 gets closer to the N-terminal in the simulation, resulting in a compact structure. This finding may provide guidance for the study on the interaction between ET-1 and ETB and the design of ET-1-based cardiovascular drugs.