(742a) Generation and Molecular Simulation of a Staphylococcus Aureus Lipid Bilayer with Lipid and Leaflet Diversity

One of the most important gram-positive bacteria that has shown high resistance against different antibiotics is Staphylococcus aureus. It has been stated that S. aureus membrane plays an important role in its resistance against antibiotics. Better understanding of S. aureus membrane will lead us to design better antibiotics. In this study, we have designed a realistic complex asymmetric S. aureus membrane by including 19 different types of lipids that are more consistent with experimental data than using single or a few lipids. These lipids are the combination of phosphatidylglycerol (PG), Lysyl-PG (L-PG), and cardiolipin (CL) headgroups and branched (anteiso and iso), saturated, and unsaturated fatty acids with different chain lengths. Reverse Monte Carlo technique was used to optimize the number of each lipid type in each leaflet on the basis of experimental results. The Force field parameters of these 19 lipids were developed by combining the force field parameters of similar lipids in the CHARMM36 library. A series of short molecular dynamics (MD) simulations, overall 10.5 ns, were conducted to equilibrate the system. Following that, 600 ns (and longer) MD simulation was applied for calculating membrane characteristics. The density profile of phosphorus and nitrogen atoms demonstrated that lipid with L-PG headgroup tended to locate closer to the center of the membrane compared to PG and CL headgroups, and the lysyl group tended to bend and orient on the (x,y) plane perpendicular to the membrane normal. The density profile of atom carbon showed the high hydrophobic tail-tail interaction at the middle of the membrane. The order parameter calculation revealed that even tails with the same type could have different order, while their trends were similar. The significant decreases were observed for the order parameter of carbons connected to iso and anteiso positions either as a branched or with a higher carbon number. Mean square displacement was calculated for each lipid type. Mean square displacement of each lipid showed diverse diffusion patterns for lipids even with the same type. Some lipids fluctuated around the same location, and some lipids diffused rapidly through the membrane parallel to the (x,y) plane. This complex membrane model revealed complicated bichemistry insights that cannot be obtained by simple models that use one or a few lipid types.