A Molecular View of the Cholesterol Condensing Effect in DOPC Lipid Bilayers

Abstract

The condensing effect of cholesterol in dioleoylphosphatidylcholine (DOPC) lipid bilayers was systematically investigated via atomistic molecular dynamics (MD) simulation. Fourteen independent 200 ns simulations, spanning the entire range of cholesterol mole fraction (xc) in DOPC bilayers (i.e. from xc = 0 to 0.66), were performed at 323 K. The molecular areas occupied by DOPC and cholesterol at different distances from the bilayer center were analyzed using a slicing method based on the VDW radii of atoms. Curiously, while the average area per lipid and the cholesterol tilt angle, in respect to the bilayer normal, both show monotonic decreases as xc increases, the average bilayer height shows a significant decrease for xc > 0.35, following an initial increase. The calculated partial-specific areas of lipids clearly show the condensing effect of cholesterol. The VDW areal analysis showed that the condensing effect is limited only to the cholesterol sterol ring region, where the acyl chains of DOPC are severely compressed by cholesterol. As xc increases, the headgroups of DOPC gradually expand along the bilayer-aqueous interface to occupy more lateral area. Thus, it confirmed a key prediction of the Umbrella model. At high cholesterol mole fractions, the calculated area per DOPC and area per cholesterol using some existing methods showed an inconsistent result: Both increase, while the overall area per lipid decreases. The inconsistency stems from the problematic assumption that cholesterol and DOPC have cylindrical shape and the same height. Our results showed that the total area of a PC/cholesterol bilayer is primarily determined by the molecular packing in the cholesterol sterol ring region. An alternative analysis of area per molecule within this region is proposed, which takes into account the cholesterol tilt angle and the practical incompressibility of cholesterol sterol rings. The new calculation shows that the majority of the area lost due to the cholesterol condensing effect is taken from PC molecules.

Alteration of lipid membrane structure and dynamics by diacylglycerols with unsaturated chains

“…The thickness of POPC/18.75% DOG is slightly larger than others, because the acyl chains of DOG are longer than that of DPG. Previously, we found that DPG produces the condensing effect in POPC bilayers [25], similar to cholesterol [51]. Based on the data in Table 1, together with the increase of acyl chain order parameter by DAG in the next section, we can conclude that all three diacylglycerols produce the condensing effect in POPC bilayers.…”

“…4a show that the addition of any type of DAG produces a similar effect to the bilayer: The POPC profiles expand in the direction of bilayer normal, indicating an increase of bilayer thickness due to the condensing effect. Furthermore, the two peaks for POPC headgroups become sharper, indicating that POPC headgroups become more ordered and more parallel to the bilayer-aqueous interfaces [51]. The electron density profiles for DPG, POG and DOG in Fig.…”

Influence of the sterol aliphatic side chain on membrane properties: a molecular dynamics study

“…This approach was carried out also in the latter case of mixtures of two major components for two reasons: (i) analysis of binary systems is more complicated, and more advanced approaches are needed; [55][56][57][58][59] and (ii) our objective was solely to verify convergence of the simulations and to compare the values obtained for the different sterols in the series, using all the same procedure. 60,61 Fig.…”

Molecular Dynamics Simulation Study of Skin Lipids: Effects of the Molar Ratio of Individual Components over a Wide Temperature Range

“…In bilayer simulation the area per lipid is a primary parameter which is directly correlated to the molecular organisation of lipid bilayer. 28 It can be compared with experiments as well as it gives information about the equilibration of the system in simulation. We have modified the method of Hofsäß et al 29 to calculate 4 the area per lipid in the mixed bilayer.…”