Aggregation of Lipid-Anchored Full-Length H-Ras in Lipid Bilayers: Simulations with the MARTINI Force Field
Aggregation of Lipid-Anchored Full-Length H-Ras in Lipid Bilayers: Simulations with the MARTINI Force Field
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DOI：
10.1371/journal.pone.0071018
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发表时间：
2013-07-26
期刊：
影响因子：
3.7
通讯作者：
Gorfe, Alemayehu A.
中科院分区：
文献类型：
--
作者：
Li, Hualin;Gorfe, Alemayehu A.
脂质锚定的Ras癌蛋白在质膜上组装成瞬时的、纳米尺寸的亚结构。这些被称为纳米簇的亚结构被认为对细胞内高保真信号传递至关重要。然而，Ras纳米簇集的分子基础知之甚少。在这项工作中，我们使用粗粒化（CG）分子动力学模拟来研究全长H - ras蛋白在模型膜中形成纳米簇的分子机制。我们选择了H - ras的两种不同构象，它们被认为分别代表蛋白质的活性和非活性状态，以及一个由二棕榈酰磷脂酰胆碱（DPPC）、二亚油酰磷脂酰胆碱（DLiPC）和胆固醇组成的具有结构域的模型双层膜。我们发现，无论初始构象如何，Ras分子都会组装成一个大的聚集体。然而，这两种结合模式（其特征在于G结构域相对于膜的不同取向）在聚集过程中和聚集之后的动力学和组织方式上有所不同。其中一些差异涉及Ras中对效应物/调节剂结合很重要的区域，这可能部分解释了观察到的活性和非活性H - ras纳米簇招募效应物能力的差异。模拟还揭示了CG力场在研究溶液中蛋白质组装方面的一些局限性，我们在提出的潜在改进途径的背景下对此进行了讨论。
Lipid-anchored Ras oncoproteins assemble into transient, nano-sized substructures on the plasma membrane. These substructures, called nanoclusters, were proposed to be crucial for high-fidelity signal transmission in cells. However, the molecular basis of Ras nanoclustering is poorly understood. In this work, we used coarse-grained (CG) molecular dynamics simulations to investigate the molecular mechanism by which full-length H-ras proteins form nanoclusters in a model membrane. We chose two different conformations of H-ras that were proposed to represent the active and inactive state of the protein, and a domain-forming model bilayer made up of di16:0-PC (DPPC), di18:2-PC (DLiPC) and cholesterol. We found that, irrespective of the initial conformation, Ras molecules assembled into a single large aggregate. However, the two binding modes, which are characterized by the different orientation of the G-domain with respect to the membrane, differ in dynamics and organization during and after aggregation. Some of these differences involve regions of Ras that are important for effector/modulator binding, which may partly explain observed differences in the ability of active and inactive H-ras nanoclusters to recruit effectors. The simulations also revealed some limitations in the CG force field to study protein assembly in solution, which we discuss in the context of proposed potential avenues of improvement.