A New Method for Biomembrane Simulations

描述（由申请人提供）：该竞争性更新申请致力于继续开发和应用一种独特而强大的多尺度计算方法来描述膜和膜过程。该项目涉及使用“自下而上”的方法，能够将分子尺度行为转化为新兴的介观尺度现象的尺度的严格桥接。广泛的原子分子动力学模拟，沿着与新的增强采样方法，被用来系统地开发强大的和一致的多尺度粗粒度（MS-CG）模型在所需的分辨率水平。MS-CG方法是上一个资助期间的关键突破，比全原子模拟的计算效率高出几个数量级，反过来又用于以多尺度方式系统地构建介观模拟模型。后者模型允许更大的长度和时间尺度的膜现象被准确地模拟。该项目的具体目标是：（目标1）继续发展用于描述现实异质膜和膜结合蛋白质的变革性多尺度模拟方法，目标是使计算机模拟与真实的生物膜的流体镶嵌图更直接相关;（2）与实验者密切合作，将多尺度模拟方法应用于由BAR结构域和ENTH结构域蛋白模块驱动的大尺度膜重构现象;（3）将混合分辨率全原子/粗粒度模拟方法应用于HIV-1 Gag多蛋白的基质结构域（MA）和大电导机械敏感通道（MscL）的膜结合和聚集，再次与实验研究合作和密切联系。该项目的总体长期目标是开发和应用一种强大的，系统的，严格的多尺度计算方法来研究生物现实的膜和膜蛋白相关现象。 公共卫生相关性：该项目涉及生物膜系统的新型多尺度计算机模拟方法的开发和应用。待研究的靶系统在罕见的神经系统自身免疫性疾病、伴乳腺癌的副肿瘤性僵硬人综合征、阿尔茨海默病、亨廷顿病、化脓性关节炎、流感病毒进入、听力、本体感受和渗透调节的生理基础以及HIV-1病毒复制的晚期发挥作用。

DESCRIPTION (provided by applicant): This competing renewal application is devoted to the continued development and application of a unique and powerful multiscale computational approach to describe membranes and membrane processes. The project involves the rigorous bridging of scales using a "bottom-up" approach that is capable of translating molecular scale behavior into emergent mesoscopic scale phenomena. Extensive atomistic molecular dynamics simulations, along with novel enhanced sampling methods, are utilized to systematically develop powerful and thermodynamically consistent multiscale coarse-grained (MS-CG) models at the desired level of resolution. The MS-CG approach, which was a key breakthrough during the last funding period and is several orders of magnitude more computationally efficient than all-atom simulations, is in turn used to systematically construct mesoscopic simulation models in a multiscale fashion. The latter models allow for even larger length and time scale membrane phenomena to be accurately simulated. The Specific Aims of this project are: (Aim 1) the continued development of the transformative multiscale simulation methodology for the description of realistic heterogeneous membranes and membrane bound proteins, with a goal of making computer simulation more directly relevant to the fluid mosaic picture of real biological membranes; (Aim 2) the application of the multiscale simulation methodology to large scale membrane remodeling phenomena, driven by BAR domain and ENTH domain protein modules, in close collaboration with experimentalists; and (Aim 3) the application of mixed resolution all-atom/coarse-grained simulation methods to the membrane binding and aggregation of the matrix domain (MA) of the HIV-1 Gag polyprotein and the mechanosensitive channel of large conductance (MscL), again in collaboration and close contact with experimental research. The overarching long term goal of this project is to develop and apply a powerful, systematic, and rigorous multiscale computational approach to the study of biologically realistic membranes and membrane protein associated phenomena. PUBLIC HEALTH RELEVANCE: Statement The project concerns the development and application of novel multiscale computer simulation methods for biomembrane systems. The target systems to be studied play a role in rare neurologic autoimmune disease, paraneoplastic Stiff-Man syndrome with breast cancer, Alzheimer's disease, Huntington's disease, pyogenic arthritis, influenza virus entry, the physiological basis for hearing, proprioception, and osmotic regulation, and the late stage of HIV-1 virus replication.