Cholesterol Flip-flop And Chemical Potential In A Systematic Set Of Lipid Bilayers

Abstract

Cholesterol is a necessary component of animal cellular membranes. The concentration of cholesterol varies from 0-5 mol% in the endoplasmic reticulum to 25-40mol% in the plasma membrane. Thermal fluctuations cause cholesterol to move normal to the plane of the bilayer. At the extremes, cholesterol can translocate across the bilayer (flip-flop) and diffuse from the bilayer into water (desorption). We have used atomistic and coarse grained molecular dynamics computer simulations to investigate the partitioning of cholesterol through a systematic set of lipid bilayers. Atomistic simulations provide detailed analysis, while inexpensive coarse grained simulations allow more bilayers to be investigated and longer time scales to be sampled. From the coarse grained simulations, cholesterol flip-flop was directly observed, and the rate matched our estimate from the free energy barrier. We find the rate of cholesterol flip-flop is fast and strongly dependent on the structure of the bilayer. The rate of flip-flop is on the microsecond range in fluid, disordered poly-unsaturated bilayers, and on the second range in rigid, ordered bilayers with high cholesterol content. The chemical potential of cholesterol in the bilayer compared to water is equal to our free energies of desorption. We can infer the relative affinity of cholesterol for the bilayers by comparing the chemical potentials. We find cholesterol prefers more ordered and rigid bilayers with saturated acyl tails, and high cholesterol content. Cholesterol has the lowest affinity for poly-unsaturated lipids.