A New Method for Biomembrane Simulations

描述（由申请人提供）：这一竞争性更新申请致力于持续发展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”的方法进行严格的尺度桥接，该方法能够将分子尺度的行为转化为新兴的介观尺度现象。广泛的原子分子动力学模拟，以及新的增强采样方法，被用来系统地开发强大的和热力学一致的多尺度粗粒度（MS-CG）模型，在所需的分辨率水平。MS-CG方法在上一个资助期间取得了重大突破，其计算效率比全原子模拟高出几个数量级，可用于系统地构建多尺度的介观模拟模型。后一种模型允许更大的长度和时间尺度的膜现象被精确地模拟。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的变革性多尺度模拟方法，目标是使计算机模拟更直接地与真实生物膜的流体马赛克图像相关；（目标2）与实验人员密切合作，将多尺度模拟方法应用于BAR结构域和ENTH结构域蛋白质模块驱动的大规模膜重构现象；（目标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并密切联系。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学上真实的膜和膜蛋白相关现象。

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.