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. Our most recent paper addresses a fundamental question of lipid biophysics, critical to understand how lipid compositional complexity influences membrane mechanics: To what spatial extent does a single lipid affect the mechanical properties of the membrane that surrounds it? The work combines molecular simulations and traditional pen-and-paper derivation to infer how far a single lipid spreads its influence over the surrounding membrane. We were surprised to find that lipids with saturated tails (similar to saturated fats) orient themselves to prefer a very specific shape on the membrane. This suggests that the outer leaflet of cellular membranes (which are enriched in saturated lipids) has its composition chosen to favor short range curvature. In a further study, we apply a sophisticated theoretical technique called free energy perturbation theory to find the relative energy of individual lipids as they move between the various shapes inside the cell. This novel application of the theory revealed the limits of elastic models for understanding highly curved structures and will serve as a standard for interpreting how lipid chemistry couples to the shape of small structures.