Facilitated and Non-Gaussian Diffusion of Cholesterol in Liquid Ordered Phase Bilayers Depends on the Flip-Flop and Spatial Arrangement of Cholesterol

The diffusion of cholesterol in biological membranes is critical to cellular processes such as the formation of cholesterol-enriched domains. The cholesterol diffusion may be complicated especially when cholesterol flip-flops and/or stays at the membrane center. Understanding the diffusion mechanism of cholesterol at a molecular level should be, therefore, a topic of interest. We perform molecular dynamics simulations up to 100 μs for lipid bilayers with various concentrations of cholesterol. We find that cholesterol diffusion in the liquid ordered phase depends on whether it is within leaflets or at the bilayer center, is non-Gaussian for several microseconds, and is enhanced significantly compared to that of lipids. Cholesterol at the bilayer center diffuses fast, while cholesterol in the hydrocarbon region with upright orientation diffuses relatively slowly. Such position-dependent dynamics of cholesterol leads to facilitated and non-Gaussian diffusion.