Interdomain exchange and the flip-flop of cholesterol in ternary component lipid membranes and their effects on heterogeneous cholesterol diffusion.

Abstract

Cell membranes are heterogeneous with a variety of lipids, cholesterol, and proteins and are composed of domains of different compositions. Such heterogeneous environments make the transport of cholesterol complicated: cholesterol not only diffuses within a particular domain but also travels between domains. Cholesterol also flip-flops between upper and lower leaflets such that cholesterol may reside both within leaflets and in the central region between two leaflets. How the presence of multiple domains and the interdomain exchange of cholesterol would affect the cholesterol transport, however, remains elusive. In this study, therefore, we perform molecular dynamics simulations up to 100μs for ternary component lipid membranes, which consist of saturated lipids (dipalmitoylphosphatidylcholine, DPPC), unsaturated lipids (dilinoleylphosphatidylcholine, DIPC), and cholesterol. The ternary component membranes in our simulations form two domains readily: DPPC and DIPC domains. We find that the diffusion of cholesterol molecules is much more heterogeneous and non-Gaussian than expected for binary component lipid membranes of lipids and cholesterol. The non-Gaussian parameter of the cholesterol molecules is about four times larger in the ternary component lipid membranes than in the binary component lipid membranes. Such non-Gaussian and heterogeneous transport of cholesterol arises from the interplay among the interdomain kinetics, the different diffusivity of cholesterol in different domains, and the flip-flop of cholesterol. This suggests that in cell membranes that consist of various domains and proteins, the cholesterol transport can be very heterogeneous. We also find that the mechanism of the interdomain exchange differs for different domains: cholesterol tends to exit the DIPC domain along the central region of the membrane for the DIPC-to-DPPC transition, while the cholesterol is likely to exit the DPPC domain within the membrane leaflet for the DPPC-to-DIPC transition. Also, the interdomain exchange kinetics of cholesterol for the DPPC-to-DIPC transition is up to 7.9 times slower than the DIPC-to-DPPC transition.