Study of the Cholesterol Umbrella Effect in DPPC and DOPC Bilayers by Molecular Dynamics Simulation

Abstract

The instability of cholesterol clusters in dipalmitoylphosphatidylcholine (DPPC) and dioleoylphosphatidylcholine (DOPC) lipid bilayers was investigated via atomistic Molecular Dynamics (MD) simulation. Cholesterol clusters in phosphatidylcholine (PC) bilayers are found to be very unstable and to readily disperse into cholesterol monomers. The instability may result from the difficulty for the system to prevent water exposure to cholesterol's aggregated hydrophobic bodies in a cluster. The system responds to artificially arranged cholesterol clusters in several interesting manners: (i) Cholesterol clusters quickly form a “frustum” shape to reduce water penetration through cholesterol headgroups; (ii) Many clusters bury themselves deeper into the bilayer interior, causing local bilayer deformation; (iii) Cholesterol fluctuates rapidly, both laterally and vertically to the bilayer plane, in order to escape from clusters. These fluctuations result in the disintegration of clusters, and in one incidence, a highly unusual flip-flop event of a cholesterol across the DOPC bilayer occurs. Our results show that cholesterols have a strong tendency to avoid forming clusters in lipid bilayers and that the fundamental cholesterol-cholesterol interaction is unfavorable. Furthermore, the radial distribution functions of cholesterol hydroxyl oxygen to various headgroup atoms of PC reveal that the PC headgroups surrounding cholesterol have a clear tendency to reorient and extend toward cholesterol. The range of this “Umbrella Effect” can reach up to 2-3 nm, larger than previously reported.