A Coarse Grain Model for a Lipid Membrane with Physiological Composition and Leaflet Asymmetry

Abstract

Coarse grain molecular dynamics simulations have become an important tool to study the membrane insertion and dynamic behavior of membrane proteins in lipid membranes. To generate a physiological membrane composition we used the lipid and cholesterol composition approximating that of synaptic vesicles (Takamori et al. 2006 Cell 127:831-46). Since the synaptic vesicle is a recycling organelle, its leaflet asymmetry is expected to reflect that of plasma membranes with the cytoplasmic leaflet mainly composed of phosphatidylethanolamine (PE) and phosphatidylserine (PS) and the extracellular (or intravesicular) leaflet mainly composed of phosphatidycholine (PC) and sphingomyelin (SM). Cholesterol also is distributed asymmetrically with 60-70% located in the cytoplasmic leaflet (Mondal et al. 2009 Mol.Biol.Cell 20:581–8). To generate a corresponding coarse grain membrane model we used GROMACS 4 and the MARTINI lipids POPE, POPC, POPS, PPCS (for SM), and CHOL. A 16x16x5 nm3 simulation box was generated and filled with the components of the intravesicular (IV) leaflet (36 PPCS, 180 POPC, 144 CHOL) and another simulation box with the same dimensions with those of the cytoplasmic (CP) leaflet (64 POPS, 210 POPE, 256 CHOL). The CP box was placed on top of the IV box such that there was an overlap of 0.5nm. Sterical overlaps between molecules were removed by running an energy minmization. After addition of water particles as needed, the simulations led reproducibly to self-assembly of a membrane retaining the essential asymmetric leaflet features of the membrane. About ∼82% of the IV lipids were retained in the IV leaflet and ∼70% of the CP lipids remained in the CP leaflet. Cholesterol partitioned equally between the two leaflets. Self-assembly also occurred reproducibly when a membrane protein was included. Supported by NIH grants R01GM085808, R21-NS072577, and the Wellcome Trust.