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 our recent methodology that can determine the "spatial extent" of a lipid's effect on membrane mechanics. In long, molecular simulations of lipid bilayers, we extract prominent configurations of lipid dimers (for example, in which they are hydrogen bonded, or have a strong electrostatic interaction) and isolate the spontaneous curvature of these dimers. This analysis was not possible before our published methodology. This allows us to extract the molecular mechanisms behind why membranes can adopt the shapes they do. Looking more broadly, these simulations will reveal why the cell has such a complex array of lipids, and how it uses those lipids to allow or prevent membrane shape transformations in homeostasis and disease.