Molecular Dynamics Investigation of the Ternary Bilayer Formed by Saturated Phosphotidylcholine, Sphingomyelin, and Cholesterol

Using the all-atom CHARMM36 force field, we have performed molecular dynamics simulations of the equimolar ternary dimyristoylphosphatidylcholine (DMPC)/ N-palmitoylsphingomyelin (PSM)/cholesterol bilayer. Analysis of its structural and kinetic properties has led us to the following conclusions. First, the DMPC/PSM/cholesterol bilayer features favorable interactions of cholesterol with DMPC and, particularly, PSM lipids, which are supported by hydrogen bonds. In contrast, the interactions between cholesterol molecules are strongly suppressed. Further analysis shows that about 60% of PSM molecules form hydrogen bonds with other PSM or cholesterol molecules and, to a lesser degree, with DMPC lipids. Second, local lipid packing around PSM molecules favors parallel or antiparallel alignments, resulting in the appearance of large anisotropic chain-like clusters formed by PSM lipids. In contrast, the distribution of DMPC lipids is closer to ideal, whereas the cholesterol distribution is sharply shifted toward small clusters or isolated molecules. Third, intermolecular interactions and mismatch in fatty acid tail lengths significantly slow down PSM rotational relaxation compared to that for DMPC, and PSM, but not DMPC lipids, tend to combine axial rotation with wobbling. Fourth, the analysis of cholesterol hydration indicates that lipid headgroups at most block about 30% of water molecules from reaching cholesterol, hinting at limited applicability of the umbrella model. Finally, we show that PSM and DMPC lipids predominantly exist in two equally probable conformational states, with and without a kink in their fatty acid tails. The appearance of these states is linked to the impact of cholesterol. Comparisons with previous studies allow us to delineate contributions of cholesterol, PSM, and DMPC to bilayer properties.