Over the last 40 years, we have learnt a great deal about the Ras onco-proteins. These intracellular molecular switches are essential for the function of a variety of physiological processes, including signal transduction cascades responsible for cell growth and proliferation. Molecular simulations and free energy calculations have played an essential role in elucidating the conformational dynamics and energetics underlying the GTP hydrolysis reaction catalysed by Ras. Here we present an overview of the main lessons from molecular simulations on the GTPase reaction and conformational dynamics of this important anti-cancer drug target. In the first part, we summarise insights from quantum mechanical and combined quantum mechanical/molecular mechanical simulations as well as other free energy methods and highlight consensus viewpoints as well as remaining controversies. The second part provides a very brief overview of new insights emerging from large-scale molecular dynamics simulations. We conclude with a perspective regarding future studies of Ras where computational approaches will likely play an active role.

中文翻译：

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GTPase Ras 酶活性和构象动力学的模拟研究概述

在过去的 40 年中，我们对 Ras 癌蛋白了解了很多。这些细胞内分子开关对于各种生理过程的功能至关重要，包括负责细胞生长和增殖的信号转导级联。分子模拟和自由能计算在阐明由 Ras 催化的 GTP 水解反应的构象动力学和能量学方面发挥了重要作用。在这里，我们概述了对 GTPase 反应和这一重要抗癌药物靶标的构象动力学进行分子模拟的主要经验教训。在第一部分，我们总结了来自量子力学和组合量子力学/分子力学模拟以及其他自由能方法的见解，并强调了共识观点以及剩余的争议。第二部分非常简要地概述了从大规模分子动力学模拟中出现的新见解。我们总结了未来对 Ras 研究的观点，其中计算方法可能会发挥积极作用。