Folding-based molecular simulations reveal mechanisms of the rotary motor F1-ATPase
Folding-based molecular simulations reveal mechanisms of the rotary motor F1-ATPase
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DOI：
10.1073/pnas.0509642103
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发表时间：
2006-04-04
影响因子：
11.1
通讯作者：
Takada, S
中科院分区：
文献类型：
--
作者：
Koga, N;Takada, S
生物分子机器通过通常发生在毫秒或更长时间尺度上的大的构象变化来实现它们的功能。传统的原子模拟目前只能达到微秒。在这里，我们扩展了蛋白质折叠的最小模型，提出了“开关G（o）在酒吧模型”，并使用它来模拟ATP驱动的分子马达F-1-ATP酶的旋转运动。模拟恢复了伽马子单元（转子）的单向120度旋转。旋转仅由来自α（3）β（3）亚基（定子）的空间排斥诱导，所述定子在ATIP水解期间经历构象变化。在计算机模拟中，丙氨酸诱变进一步阐明了哪些残基在旋转中发挥特定作用。最后，关于机械化学耦合方案，我们发现，三位模型不会导致成功的旋转，但总是双位模型产生约30度和约90度的子步骤，完全符合雅阁。在always-bi-site模型中，在水解循环期间，核苷酸占据的位点的数量总是两个。这项研究开辟了一条途径，模拟功能动力学的巨大的生物分子，发生在毫秒的时间尺度上，涉及大幅度的构象变化。
Biomolecular machines fulfill their function through large conformational changes that typically occur on the millisecond time scale or longer. Conventional atomistic simulations can only reach microseconds at the moment. Here, extending the minimalist model developed for protein folding, we propose the "switching G (o) over bar model" and use it to simulate the rotary motion of ATP-driven molecular motor F-1-ATPase. The simulation recovers the unidirectional 120 degrees rotation of the gamma-subunit, the rotor. The rotation was induced solely by steric repulsion from the alpha(3)beta(3) subunits, the stator, which undergoes conformation changes during ATIP hydrolysis. In silico, alanine mutagenesis further elucidated which residues play specific roles in the rotation. Finally, regarding the mechanochemical coupling scheme, we found that the tri-site model does not lead to successful rotation but that the always bi-site model produces approximate to 30 degrees and approximate to 90 degrees substeps, perfectly in accord with experiments. In the always-bi-site model, the number of sites occupied by nucleotides is always two during the hydrolysis cycle. This study opens up an avenue of simulating functional dynamics of huge biomolecules that occur on the millisecond time scales involving large-amplitude conformational change.