A Multiscale Model of Protein Mediated Changes in membrane Morphology

 描述（由申请人提供）：大量的细胞过程涉及主要的膜重塑事件，例如双层融合或断裂，这是能量昂贵的，并且需要额外的蛋白质机制来有效地进行。这是甲型流感病毒出芽的情况，最近显示需要膜嵌入的M2离子通道。在这里，我们建议开发一个多尺度的计算模型，再加上实验，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有效地将膜的动力学与膜蛋白的动力学耦合起来，后者可以小数千倍。首先，我们将构建一个灵活的，相场模型的膜在微米长度尺度的脂质成分和膜蛋白，如M2质子通道，描述了随时间变化的概率分布，扩散在膜的表面上，并影响局部膜的机械性能（目的1）。接下来，该模型将通过使用全原子和混合连续原子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中的大长度尺度模型将通过实验研究进一步参数化，实验研究将定量测量M2通道相关肽在不同有序和无序膜相之间分配的能量学（目标3）。我们的计算方法将允许在空间和时间尺度上有效地模拟膜变形和拓扑变化，这是目前使用传统方法不可能实现的。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，蛋白质结构和脂质-蛋白质相互作用的影响。我们的模拟技术将广泛适用于HIV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聚结。

 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.