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首页> 外文期刊>Proceedings of the National Academy of Sciences of the United States of America >Atomically detailed simulation of the recovery stroke in myosin by Milestoning
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Atomically detailed simulation of the recovery stroke in myosin by Milestoning

机译：Milestoning对肌球蛋白恢复冲程的原子详细模拟

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摘要

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.
机译：肌球蛋白II是一种将化学能转化为机械能并能够进行肌肉操作的分子马达。动力冲程后，恢复过渡会完成循环，并使分子电动机返回到其冲程前状态。 Milestoning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理。里程碑将过程沿着反应坐标分为超表面（里程碑）之间的过渡。假定顺序里程碑之间的动力学去相关，这将原子详细模拟的速度提高了数百万倍。具有明显水溶作用的肌球蛋白的200条轨迹用于对连续的里程碑对之间的过渡进行采样。以原子分辨率和毫秒时间尺度描述了数百个原子的集体运动。实验测量的过渡时间约为一毫秒，与计算出的时间非常吻合。仿真支持顺序机制。第一步，P环和开关2在ATP上闭合，第二步，通过继电器和SH1螺旋引起机械松弛。我们建议开关2的熵有助于驱动功率冲程。二级结构元素通过激活的跃迁网络中的少量离散状态而发展，并通过在互变异构状态之间的侧链翻转来辅助。少数状态顺序机制可能会提高松弛效率，从而减少偏离路径的中间体的可能性。

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