Interdependence of cholesterol distribution and conformational order in lipid bilayers.

This article investigates the interdependence between cholesterol localization and lipid order within phospholipid bilayers using molecular simulations. Employing the Dry Martini coarse-grained force field, validated against the Wet Martini force field and experimental data, the study examines three lipid bilayer systems—DOPC/CHOL, 20:0SM/CHOL, and DOPC/20:0SM/CHOL—across varying cholesterol concentrations and temperatures. The findings reveal that cholesterol preferentially localizes in the bilayer leaflets and aligns parallel to the bilayer normal in the ordered phase, whereas in the disordered phase, cholesterol resides near the bilayer midplane with an orientation more orthogonal to the bilayer normal. Notably, the melting temperature (Tm) of the bilayers coincides with the temperature (Tcross) at which cholesterol distribution between leaflets and midplane is equal, indicating that lipid order primarily governs cholesterol localization. These results highlight a reciprocal relationship where cholesterol induces lipid ordering, which in turn influences cholesterol positioning, with potential implications for membrane protein function and material transport in biological membranes.