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

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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.