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. 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 published work this year has focused on collaborations that are pursuing similar objectives to our own, but with complementary "wet lab" techniques that often require molecular mechanisms. With the Budin lab (UCSD), we have determined how key functional differences of sterols are determined by fine variations in their chemical structure (Juarez-Contreras et al, Science Advances). Itay's lab blocked synthesis of each step in the biosynthetic path of ergosterol in yeast, and observed the phenotypic result of lateral (lipid mediated) phase separation in the yeast's vacuole. Our simulation work recapitulated the precursor-dependence of the effect, and showed that there is an inherently non-local effect of ordering by the sterols, consistent with the nanometer-scale molecular driving force for phase separation our lab has previously proposed. In collaborative work with two other NICHD labs, we determined the structure of a previously uncharacterized P-Type ATPase, and showed that it was (unexpectedly) a dimer. Our simulations indicated the dynamics of an interior magnesium ion binding pocket beyond the cryo-EM structure, and characterized the lipid dynamics around the boundary of the protein, which cannot be inferred from detergent-derived structures.