Nano to Meso and Back Again: Capturing and Exploiting Dynamic Heterogeneities in Biological Membranes via Large Scale Simulations

膜对生物学至关重要：它们形成所有细胞的“围墙”，并控制物质和信息进出细胞的流动。膜的蛋白质嵌入在脂质双层中，脂质双层是将细胞内容物与其水性外部环境分离的油状膜。这些膜蛋白负责许多关键的生物学功能，包括细胞之间的通信，因此是许多药物的靶点，包括一些抗生素。然而，膜不仅仅是简单的“各部分的总和”。相反，它们是蛋白质和脂质的复杂和动态组装，它们的生物学功能是整个膜系统的涌现特性。这项建议的总体目标是发展各种方法来了解膜的各种成分是如何动态组织的，以便执行它们的生物学功能，可以使用组成细胞膜的相互作用分子（蛋白质和脂质）的计算机模拟来研究它们的动态行为和组织。迄今为止的模拟研究仅限于非常小的（纳米）尺度，并且集中在例如单膜蛋白与紧邻的脂质分子的相互作用上。然而，需要更大规模的模拟来解决细胞膜动态组织的（亚）细胞尺度。这些更大规模的模拟将能够直接比较从模拟与实验观察中出现的预测。我们将使用“中"尺度模型开发更大尺度的模拟，这些模型可以使用已经成功用于研究分离膜蛋白的小尺度模型和模拟的结果来构建。我们将使用先进的计算机模拟，受益于英国对国家超级计算设施的投资，以：1.发展细胞膜动态空间异质性的生物现实模型;和2。将小尺度（粗粒度）和大尺度（中尺度）模型与实验数据相结合，使我们能够在膜的结构和细胞研究之间架起桥梁。因此，这些研究的总体结果将是一个强大的新的计算机模拟方法的生物膜，这将有相关的制药和生物技术部门的应用。

Membranes are of fundamental importance to biology: they form the 'surrounding walls' of all cells, and control the flow of materials and information into and out of cells. The proteins of membranes are embedded in a lipid bilayer, which is an oil-like film separating the cellular contents from its watery external environment. These membrane proteins are responsible for many key biological functions, including communication between cells, and consequently are targets for many drugs, including some antibiotics. However, membranes are more than a simple 'sum of their parts'. Rather, they are complex and dynamic assemblies of proteins and lipids, and their biological functions are emergent properties of the membrane system as a whole. The overall aim of this proposal is to develop methods to understand how the various components of membranes are dynamically organized so as to carry out their biological functions.Computer simulations of the interacting molecules (proteins and lipids) which make up cell membranes may be used to study their dynamic behaviour and organization. Simulation studies to date have been limited to the very small (nano)scale, and have focused on e.g. the interactions of single membrane proteins with immediately neighbouring lipid molecules. However, larger scale simulations are needed to address (sub)cellular scales of the dynamic organization of cell membranes. These larger scale simulations will enable direct comparison of predictions emerging from simulations with experimental observations. We will develop larger scale simulations using 'meso' scale models which can be built using the outcomes of smaller scale models and simulations which have already been successfully employed to study isolated membrane proteins.We will use advanced computer simulations, benefiting from UK investment in national supercomputing facilities, to:1. Develop biologically realistic models of dynamic spatial heterogeneities in cell membranes; and2. Link smaller scale (coarse-grained) and larger scale (meso) models with experimental data in an integrated approach allowing us to bridge between structural and cellular studies of membranes. Thus, the overall outcome of these studies will be a powerful new computer simulation method for biological membranes, which will have applications relevant to the pharmaceutical and biotechnology sectors.