Molecular simulations of lipid curvature stress and its effect on transmembrane proteins

Eunice Kennedy Shriver National Institute Of Child Health & Human Development

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Abstract

The purpose of this project is to investigate the physical mechanisms by which the lipid membrane influences the protein functions that underlie most biological processes. A typical project in the lab identifies a hypothesis for a particular mechanism in conceptual terms, forms a mathematical or physical model for the process, then tests and refines the model using a molecular simulation. Next the project is developed to make predictions that can be tested in the laboratory.hge The projects use the NIH Biowulf computing cluster as well as custom NICHD resources to run the simulations and models. Molecular dynamics software (such as NAMD and CHARMM) are used to conduct molecular simulations. In-house software development for public distribution is a key element of the lab. Work this year has applied both our fundamental theory and methodology for how lipids and proteins affect membranes as well as our ability to build and analyze complex membrane structures that are high energy intermediates in membrane reshaping. Our theory lets us see on an individual lipid level how that lipid affects local mechanics --- and how we expect it to distribute itself on a membrane structure. This lets us determine the effect of a single lipid on mechanics, and in turn reveals how the lipid composition of biological membranes facilitates fundamental processes, such as clathrin mediated endocytosis. Additionally, we gain insight into how the lipid composition around a protein (like a G-protein coupled receptor) affects its function.