Cholesterol behavior in asymmetric lipid bilayers: insights from molecular dynamics simulations.

Asymmetric lipid composition of the cell membranes plays an important role in the multitude of important biological functions. Much less is known, however, about the distribution and dynamics of cholesterol in asymmetric biological membranes. In this work we show how this issue could be addressed computationally by molecular dynamics simulations. The influence of the lipid head group charge, acyl chain saturation, spontaneous membrane curvature and the surface tension of the membrane on cholesterol distribution in asymmetric lipid bilayers is investigated. Four asymmetric bilayers containing DOPC, DOPS, DSPC, or DSPS lipids, were simulated on the time scale extended to tens of microseconds. We show that cholesterol strongly prefers anionic lipids to neutral and saturated lipid tails to unsaturated with distribution ratio ~0.4-0.6. Multiple flip-flop transitions of cholesterol were observed directly and their mean times range from 350 to 2,000 ns. It was shown that the distribution of cholesterol in the asymmetric bilayer depends not only on the type of lipids but also on the local membrane curvature and the surface tension. The geometric shape of spontaneously curved asymmetric bilayer changes dramatically in the presence of cholesterol. The membrane curvature becomes less homogeneous with large patches of flattened regions interleaved by rather sharp bends.