Monte Carlo simulations of proton pumps: On the working principles of the biological valve that controls proton pumping in cytochrome c oxidase
Monte Carlo simulations of proton pumps: On the working principles of the biological valve that controls proton pumping in cytochrome c oxidase
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DOI：
10.1073/pnas.0510860103
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发表时间：
2006-04-25
影响因子：
11.1
通讯作者：
Warshel, A
中科院分区：
文献类型：
--
作者：
Olsson, MHM;Warshel, A
获得细胞色素c氧化酶（COX）质子泵送过程的详细了解是现代生物物理学的挑战之一。最近的突变实验强调了这一挑战，表明单个突变（N139D突变）阻断了整个泵送，同时继续将质子输送到双核中心，而不抑制氧化酶的活性。使这一结果合理化一直是一个主要问题，因为突变离E286很远，而E286被认为是泵送过程中质子输运的分支点。在缺乏对这一重要观察的合理解释的情况下，我们开发了一种蒙特卡罗模拟方法，可以将突变和结构信息转换为质子易位的途径，并在毫秒甚至亚秒的时间尺度上模拟COX中的泵送过程。该工具使我们能够重现并提出N139D突变效应的可能解释，并为COX中“阀效应”的起源提供一致的模型，这对于维持上坡质子泵至关重要。此外，获得COX或任何其他蛋白质中质子泵浦的第一个基于结构的模拟表明，我们的方法应该为验证关于质子运输蛋白质作用的机制假设提供有力的工具。
Gaining a detailed understanding of the proton-pumping process in cytochrome c oxidase (COX) is one of the challenges of modern biophysics. Recent mutation experiments have highlighted this challenge by showing that a single mutation (the N139D mutation) blocks the overall pumping while continuing to channel protons to the binuclear center without inhibiting the oxidase activity. Rationalizing this result has been a major problem because the mutation is quite far from E286, which is believed to serve as the branching point for the proton transport in the pumping process. In the absence of a reasonable explanation for this important observation, we have developed a Monte Carlo simulation method that can convert mutation and structural information to pathways for proton translocation and simulate the pumping process in COX on a millisecond and even subsecond time scale. This tool allows us to reproduce and propose a possible explanation to the effect of the N139D mutation and to offer a consistent model for the origin of the "valve effect" in COX, which is crucial for maintaining uphill proton pumping. Furthermore, obtaining the first structure-based simulation of proton pumping in COX, or in any other protein, indicates that our approach should provide a powerful tool for verification of mechanistic hypotheses about the action of proton transport proteins.