Capturing spontaneous partitioning of peripheral proteins using a biphasic membrane-mimetic model.
Capturing spontaneous partitioning of peripheral proteins using a biphasic membrane-mimetic model.
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DOI：
10.1021/jp109631y
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发表时间：
2011-06-02
期刊：
影响因子：
--
通讯作者：
Tajkhorshid E
中科院分区：
文献类型：
--
作者：
Arcario MJ;Ohkubo YZ;Tajkhorshid E
由专门的锚定结构域介导的外周蛋白的膜结合是其生物学功能的关键步骤。然而，膜插入的计算研究已被证明是具有挑战性的，并且在很大程度上是不可访问的，这是由于完整描述该过程所需的时间尺度，主要是由组成膜的脂质分子的缓慢扩散引起的。此外，在许多情况下，膜“锚”的性质，即，插入细胞膜的蛋白质部分也是未知的。在这里，我们解决了一些这些问题，通过开发和采用一个简化的表示膜的两相溶剂模型，我们证明可以有效地用于捕获和描述的疏水插入的过程中的膜锚定结构域的全原子分子动力学模拟。应用该模型，我们研究了插入的锚定结构域的凝固蛋白（GLA域的人蛋白C），从多个初始配置不同的初始方向和高度的蛋白质相对于膜。除了有效和一致地将“龙骨”区域识别为疏水膜锚之外，在几纳秒内，每个模拟的配置显示出相对于界面法线的会聚高度（2.20 ± 1.04 °）和角度（23.37 ± 12.48°）。我们证明，该模型可以产生相同的结果，从一个完整的表示膜，在渗透的深度和蛋白质的方向在最终的膜结合的形式与一个数量级减少所需的计算时间相比，以前的模型，允许一个更详尽的搜索正确的膜结合的配置。
Membrane binding of peripheral proteins, mediated by specialized anchoring domains, is a crucial step for their biological function. Computational studies of membrane insertion, however, have proven challenging and largely inaccessible, due to the time scales required for the complete description of the process, mainly caused by the slow diffusion of the lipid molecules composing the membrane. Furthermore, in many cases, the nature of the membrane “anchor”, i.e., the part of the protein that inserts into the membrane, is also unknown. Here, we address some of these issues by developing and employing a simplified representation of the membrane by a biphasic solvent model which we demonstrate can be used efficiently to capture and describe the process of hydrophobic insertion of membrane anchoring domains in all-atom molecular dynamics simulations. Applying the model, we have studied the insertion of the anchoring domain of a coagulation protein (the GLA domain of human protein C), starting from multiple initial configurations varying with regard to the initial orientation and height of the protein with respect to the membrane. In addition to efficiently and consistently identifying the “keel” region as the hydrophobic membrane anchor, within a few nanoseconds each configuration simulated showed a convergent height (2.20 ± 1.04 Å) and angle with respect to the interface normal (23.37 ± 12.48°). We demonstrate that the model can produce the same results as those obtained from a full representation of a membrane, in terms of both the depth of penetration and the orientation of the protein in the final membrane-bound form with an order of magnitude decrease in the required computational time compared to previous models, allowing for a more exhaustive search for the correct membrane-bound configuration.
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