Atomically detailed simulation of the recovery stroke in myosin by Milestoning
Atomically detailed simulation of the recovery stroke in myosin by Milestoning
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DOI：
10.1073/pnas.0909636107
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发表时间：
2010-03-16
影响因子：
11.1
通讯作者：
West, Anthony
中科院分区：
文献类型：
--
作者：
Elber, Ron;West, Anthony
肌球蛋白 II 是一种分子马达，可将化学能转化为机械能并实现肌肉运作。动力冲程后，恢复过渡完成循环并使分子马达返回到其预冲程状态。里程碑理论框架中的原子详细模拟用于计算恢复冲程的动力学和机制。里程碑将过程划分为沿着反应坐标的超曲面（里程碑）之间的转变。假设连续里程碑之间的动力学去相关，这将原子详细的模拟速度提高了数百万倍。使用具有明确水溶剂化作用的 200 个肌球蛋白轨迹来对连续的里程碑对之间的转变进行采样。以原子分辨率和毫秒时间尺度描述数百个原子的集体运动。实验测量的大约一毫秒的过渡时间与计算的时间非常吻合。模拟支持顺序机制。在第一步中，P 环路和开关 2 在 ATP 上闭合，在第二步中，通过继电器和 SH1 螺旋诱导机械松弛。我们建议开关 2 的熵有助于驱动做功冲程。二级结构元件在激活转变网络中通过少量离散状态前进，并通过旋转异构体状态之间的侧链翻转来协助。少状态顺序机制可能会提高松弛的效率，从而减少偏离路径中间体的可能性。
Myosin II is a molecular motor that converts chemical to mechanical energy and enables muscle operations. After a power stroke, a recovery transition completes the cycle and returns the molecular motor to its prestroke state. Atomically detailed simulations in the framework of the Milestoning theory are used to calculate kinetics and mechanisms of the recovery stroke. Milestoning divides the process into transitions between hyper-surfaces (Milestones) along a reaction coordinate. Decorrelation of dynamics between sequential Milestones is assumed, which speeds up the atomically detailed simulations by a factor of millions. Two hundred trajectories of myosin with explicit water solvation are used to sample transitions between sequential pairs of Milestones. Collective motions of hundreds of atoms are described at atomic resolution and at the millisecond time scale. The experimentally measured transition time of about a millisecond is in good agreement with the computed time. The simulations support a sequential mechanism. In the first step the P-loop and switch 2 close on the ATP and in the second step the mechanical relaxation is induced via the relay and the SH1 helices. We propose that the entropy of switch 2 helps to drive the power stroke. Secondary structure elements are progressing through a small number of discrete states in a network of activated transitions and are assisted by side chain flips between rotameric states. The few-state sequential mechanism is likely to enhance the efficiency of the relaxation reducing the probability of off-pathway intermediates.