A Multiscale Model of Protein Mediated Changes in membrane Morphology

 描述(申请人提供)：大量的细胞过程涉及主要的膜重塑事件，如双层融合或断裂，这是能量昂贵的，需要额外的蛋白质机械才能有效地进行。这就是甲型流感病毒萌芽的情况，最近被证明需要膜嵌入M2离子通道。在这里，我们建议开发一个多尺度计算模型，结合实验，定量研究蛋白质介导的膜形态的大规模变化。基本的计算挑战是准确和有效地将膜的动力学与膜蛋白的动力学耦合起来，膜蛋白质的动力学可以小几千倍。首先，我们将在微米尺度上构建一个灵活的膜相场模型，在该模型中，脂类成分和膜蛋白，如M2质子通道，通过扩散到膜表面并影响局部膜机械性能的随时间变化的概率分布来描述(目标1)。接下来，模型将通过使用完全原子化和混合连续原子化方法在纳米尺度上进行参数化，以揭示单个M2通道如何改变膜特性(目标2)。最后，目标1中的大尺度模型将通过实验研究进一步参数化，该实验将定量测量M2通道相关多肽在不同有序和无序膜相之间分配的能量(目标3)。我们的计算方法将允许有效地模拟薄膜在空间和时间尺度上的变形和拓扑变化，这是目前使用传统方法无法实现的。我们的综合计算和实验分析将解决与蛋白质驱动的膜曲率相关的基本生物物理和医学问题，并将阐明这些过程如何受到脂质组成、蛋白质结构和脂蛋白相互作用的影响。我们的模拟技术将广泛适用于艾滋病毒和埃博拉病毒使用的病毒退出步骤，以及这类病毒的初始进入步骤，这涉及病毒和宿主细胞膜的蛋白质介导的结合。

 DESCRIPTION (provided by applicant): A large number of cellular processes involve major membrane remodeling events, such as bilayer fusion or scission, which are energetically costly and require additional protein machinery to proceed efficiently. This is the case for influenza A virus budding, which was recently shown to require the membrane embedded M2 ion channel. Here, we propose to develop a multiscale computational model, coupled with experiments, to quantitatively study protein-mediated large-scale changes in membrane morphology. The fundamental computational challenge is to accurately and efficiently couple the dynamics of the membrane to those of the membrane proteins, which can be thousands of times smaller. First, we will construct a flexible, phase field model of the membrane at the micrometer length scale in which lipid components and membrane proteins, such as the M2 proton channel, are described by time-dependent probability distributions that diffuse on the surface of the membrane and influence the local membrane mechanical properties (Aim 1). Next, the model will be parameterized at the nanometer scale through the use of fully-atomistic and hybrid continuum-atomistic methods to reveal how individual M2 channels alter membrane properties (Aim 2). Finally, the large-length scale model in Aim 1 will be further parameterized through experimental studies that will quantitatively measure the energetics of M2 channel related peptides partitioning between different ordered and disordered membrane phases (Aim 3). Our computational approach will allow efficient simulations of membrane deformation and topological changes on spatial and temporal scales that are not currently possible using conventional methodologies. Our integrated computational and experimental analysis will address fundamental biophysical and medical questions related to protein driven membrane curvatures, and it will elucidate how these processes are affected by lipid composition, protein structure, and lipid-protein interactions. Our simulation techniques will have widespread applicability to the viral exit step used by HIV and Ebola as well as the initial entry step for ths class of viruses, which involves protein-mediated coalescence of the viral and host cell membranes.