Step-Wise Hydration of Magnesium by Four Water Molecules Precedes Phosphate Release in a Myosin Motor.
Step-Wise Hydration of Magnesium by Four Water Molecules Precedes Phosphate Release in a Myosin Motor.
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在肌球蛋白运动中磷酸盐释放之前，四个水分子对镁的逐步水合。
DOI：
10.1021/acs.jpcb.0c10004
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发表时间：
2021
期刊：
影响因子：
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通讯作者：
Thirumalai,D
中科院分区：
文献类型：
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作者：
Mugnai,MauroLorenzo;Thirumalai,D
分子马达，如肌凝蛋白、运动蛋白和动力蛋白，将ATP水解释放的能量转化为机械功，从而使它们能够在细胞骨架轨道上进行定向运动。肌球蛋白马达化学机械转导的关键步骤发生在它们与肌动蛋白丝结合后，这触发磷酸盐（Pi， ATP水解产物）的释放和杠杆臂的旋转。在这里，我们通过广泛的分子动力学模拟研究了磷酸在肌凝蛋白VI中释放的机制，涉及几个μs的多个轨迹。因为在肌凝蛋白VI中，磷酸盐的逃逸预计会在毫秒或更长时间尺度上发生，所以我们只观察到磷酸释放的轨迹是由核苷酸结合口袋内的旋转磷酸启动的。我们发现，尽管pii占据了传统的“后门”路线，但磷酸盐通过各种其他门户退出，从而建立了逃逸路线的异质性。值得注意的是，我们观察到磷酸盐的释放是由adp结合的镁离子的逐步水化引起的。只有在四个水分子与阳离子（Mg2+）水合后，阴离子才会释放出来。通过比较结构分析，我们发现镁的水合作用是许多atp酶和gtp酶中磷酸盐释放的关键步骤。大自然可能已经进化出Mg2+的水合作用，作为Pirelease的一般分子开关，Pirelease是许多机器催化循环中具有很少序列或结构相似性的普遍步骤。
Molecular motors, such as myosin, kinesin, and dynein, convert the energy released by the hydrolysis of ATP into mechanical work, thus allowing them to undergo directional motion on cytoskeletal tracks. A pivotal step in the chemomechanical transduction in myosin motors occurs after they bind to the actin filament, which triggers the release of phosphate (Pi, product of ATP hydrolysis) and the rotation of the lever arm. Here, we investigate the mechanism of phosphate release in myosin VI using extensive molecular dynamics simulations involving multiple trajectories of several μs. Because the escape of phosphate is expected to occur on time-scales on the order of milliseconds or more in myosin VI, we observed Pirelease only if the trajectories were initiated with a rotated phosphate inside the nucleotide binding pocket. We discovered that although Pipopulates the traditional “back door” route, phosphate exits through various other gateways, thus establishing the heterogeneity in the escape routes. Remarkably, we observed that the release of phosphate is preceded by a stepwise hydration of the ADP-bound magnesium ion. The release of the anion occurred only after four water molecules hydrated the cation (Mg2+). By performing comparative structural analyses, we show that hydration of magnesium is the key step in the phosphate release in a number of ATPases and GTPases. Nature may have evolved hydration of Mg2+as a general molecular switch for Pirelease, which is a universal step in the catalytic cycle of many machines that share little sequence or structural similarity.