(581d) Computational Study of Lipid Dynamics within a Complex Realistic Staphylococcus Aureus Membrane with Lipid and Leaflet Diversity

Staphylococcus aureus is a gram-positive bacterial species that has a high resistance against diverse antibiotics. Studies have pointed out an influential role of its membrane in the resistance of S. aureus to antibiotics. In this study, we modeled a realistic and complex S. aureus lipid bilayer to reveal detailed insights into lipid structure and dynamics, which can lead to model-based design of more effective antibiotics. To represent the diversity of head groups and fatty acid tails known from experimental data within a tractable simulation model, 19 different lipid types consisting of phosphatidylglycerol (PG), Lysyl-PG (L-PG), and cardiolipin (CL) head groups combined with branched (anteiso and iso), saturated, and unsaturated fatty acid tail moieties having different chain lengths were selected. The number of each lipid type in each leaflet was optimized on the basis of experimental lipid composition data by a reverse Monte Carlo technique. Force field parameters of these lipids were developed by combining similar lipids already present in the CHARMM36 library. Molecular Dynamics (MD) simulations were conducted to equilibrate the system (10.5 ns) and to calculate static and dynamic membrane properties (650 ns). Ensemble averages for the density profiles of atoms and CH₃ groups of lipids and for the order parameter along the length of each lipid tail were calculated as static characteristics. These results demonstrated that (1) there is a high hydrophobic tail-tail interaction in the middle of the lipid bilayer, and (2) C-H bond order parameter decreased away from the head group with increased distance into the bilayer, and a larger decrease in ordering occurred for C-H bonds connected to iso and anteiso positions in a branch or in a methylene group further along the backbone. Mean-squared displacements (MSD) were averaged for each lipid type, and the self-diffusion coefficient of each lipid type was calculated using the Einstein diffusion relationship. MSDs showed a distribution of diffusion rates for lipids of the same type within the membrane. The time autocorrelation function of the vector between phosphorus and the carbon at the end of each tail (P-C vector) of all lipids was calculated to study local fluidity within each leaflet. A Fourier transformation (FT) method was applied to incorporate the full extent of lipid fluctuation details into the time autocorrelation function calculations. These results demonstrated that individual lipid molecules displayed a diverse range of relaxation rates, even within the same lipid type; however, tails that move slowly have longer relaxation and reorientation times. This complex bilayer model contributes to understanding the dynamic biochemistry and biophysics of typical S. aureus lipid bilayers at a detailed level that cannot be achieved using simpler bilayer models that are composed only using limited types of lipid building blocks.