School of Biomedical Engineering, Guangdong Medical University, Dongguan 523808, China.
Collaborative Innovation Center of Chemistry for Energy Materials, Shanghai Key Laboratory of Molecular Catalysis and Innovative Materials, MOE Key Laboratory of Computational Physical Sciences, Departments of Chemistry, Fudan University, Shanghai 200433, China.
J Phys Chem B. 2021 Aug 12;125(31):8805-8813. doi: 10.1021/acs.jpcb.1c04679. Epub 2021 Jul 29.
The Ras protein is one of the most important drug targets for battling cancers. To effectively design novel drugs of Ras, we characterize here its conformational ensembles for the hydrolysis intermediate state RasGDP·Pi and the product state RasGDP by extensive replica-exchange molecular dynamics simulations. Several substates for RasGDP·Pi have been identified, while structural analyses have revealed an unrecognized hydrogen-bonding network that stabilizes the hydrolysis intermediate state. More interestingly, Gln61, which is involved in numerous oncogenic mutations, was found to be engaged in this hydrogen-bonding network, adopting a specific conformation that always points to Pi in contrast to that in the RasGTP state. The simulations also reveal that RasGDP has more than one substate, suggesting a conformational selection mechanism for the interaction between Ras and the guanine nucleotide exchange factors (GEFs). These findings offer new opportunities for the drug design of Ras by stabilizing the hydrolysis intermediate or disrupting its interaction with the GEFs.
Ras 蛋白是抗癌药物的最重要靶点之一。为了有效地设计新型 Ras 药物，我们通过广泛的复制交换分子动力学模拟对其水解中间态 RasGDP·Pi 和产物态 RasGDP 的构象集合进行了表征。已经鉴定出 RasGDP·Pi 的几个亚态，而结构分析揭示了一个未被识别的氢键网络，该网络稳定了水解中间态。更有趣的是，参与众多致癌突变的 Gln61 被发现参与了这个氢键网络，采用了一种特定的构象，与 RasGTP 状态相反，总是指向 Pi。模拟还表明 RasGDP 有不止一种亚态，这表明 Ras 与鸟嘌呤核苷酸交换因子（GEFs）之间的相互作用存在构象选择机制。这些发现为通过稳定水解中间态或破坏其与 GEFs 的相互作用来设计 Ras 药物提供了新的机会。
