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”，并控制物质和信息的进出细胞。膜上的蛋白质被包埋在脂质双层中，这是一层油状的薄膜，将细胞内容物与其潮湿的外部环境隔开。这些膜蛋白负责许多关键的生物学功能，包括细胞之间的通讯，因此是许多药物的靶标，包括一些抗生素。然而，膜不仅仅是它们各部分的简单总和。相反，它们是蛋白质和脂类的复杂和动态的集合，它们的生物学功能是膜系统作为一个整体的紧急特性。这一建议的总体目标是开发方法来了解膜的各种成分是如何动态组织的，从而执行其生物功能。对构成细胞膜的相互作用的分子(蛋白质和脂)的计算机模拟可用于研究它们的动态行为和组织。到目前为止，模拟研究一直局限于非常小的(纳米)尺度，并集中在例如单膜蛋白与紧邻的脂类分子的相互作用上。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使从模拟中产生的预测与实验观测直接进行比较。我们将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开发更大规模的模拟，这些模型可以使用较小尺度的模型和模拟来建立。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.开发细胞膜动态空间异质性的生物逼真模型；以及2.将小尺度(粗粒度)和大尺度(中观)模型与实验数据以一种综合的方法联系起来，使我们能够在膜的结构研究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种强大的新的生物膜计算机模拟方法，它将在制药和生物技术部门得到应用。

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.