Comparative molecular dynamics study of lipid membranes containing cholesterol and ergosterol

Abstract

Sterol molecules are essential for maintaining the proper structure and function of eukaryotic cell membranes. The influence of cholesterol (the principal sterol of higher animals) on the lipid bilayer properties was extensively studied by both experimental and simulation methods. In contrast, the effect of ergosterol (the principal fungal sterol) on the membrane structure and dynamics is much less recognized. This work presents the results of comparative molecular dynamics simulation of the hydrated dimyristoylphosphatidylcholine bilayer containing approximately 25 mol % of cholesterol or ergosterol. A detailed analysis of the molecular properties (e.g., bilayer thickness, lipid order, diffusion, intermolecular interactions, etc.) of both sterol-induced liquid-ordered membrane phases is presented. Presence of sterols in the membrane significantly changes its property, especially fluidity and molecular packing. Moreover, in accordance with the experiments, our calculations show that, compared to cholesterol, ergosterol has higher ordering effect on the phospholipid acyl chains. This different influence on the properties of the lipid bilayer stems from differences in conformational freedom of sterol side chains. Additionally, obtained models of lipid membranes containing human and fungal sterols, constituting the result of our work, can be also utilized in other chemotherapeutic studies on interaction of selected ligands (e.g., antifungal compounds) with membranes.

FIGURE 1

Structure of cholesterol (A) and ergosterol (B) molecules. Definitions of distinguished dihedral angles are the following: α ≡ (C14–C17–C20–C22), β ≡ (C17–C20–C22–C23), γ ≡ (C20–C22–C23–C24), δ ≡ (C22–C23–C24–C25), and ɛ ≡ (C23–C24–C25–C27).

FIGURE 2

The electron density profiles of the simulated systems along the bilayer normal. Experimental profile for pure DMPC bilayer is taken from Kucerka et al. (57).

FIGURE 3

Individual components of the electron density profiles along the bilayer normal in the simulated systems: DMPC molecules (solid line), sterol ring system (dashed line), sterol side chain (dotted line), and water molecules (symbols only; no line).

FIGURE 4

Electron densities of various groups across the DMPC/Chol (a) and DMPC/Erg (b) bilayer: DMPC trimethylammonium groups (▴), DMPC phosphate groups (▪), DMPC carbonyl groups (•), DMPC terminal methyl groups (Δ), sterol hydroxyl groups (□), and sterol terminal isopropyl group (○).

FIGURE 5

Profiles of the deuterium order parameter calculated for the DMPC sn-1 (solid line) and sn-2 (dashed line) in the simulated systems. Experimental values averaged over both DMPC acyl chains are taken from Petrache et al. (58).

FIGURE 6

Distributions of the sterol tilt angles calculated separately for the sterol ring system and sterol side chains in the simulated systems. Tilts are defined as angles formed between the C17→C3 (ring system tilt) or C25→C17 (side-chain tilt) vectors and the bilayer normal.

FIGURE 7

Distributions of the selected dihedral angles in the Chol (a) and Erg (b) side chains. Additionally, schematic images of sterol molecules were shown next to the corresponding plots.

FIGURE 8

Distribution of the angle between P→N vector and the bilayer normal in the simulated systems: pure DMPC (solid line), DMPC/Chol (dashed line), and DMPC/Erg (dotted line).

FIGURE 9

Radial distribution functions between the DMPC nitrogen atom and selected atoms from other molecules calculated in pure DMPC (a), DMPC/Chol (b), and DMPC/Erg (c) systems; DMPC phosphorus atom (solid line), hydrogen atom in the sterol hydroxyl group (dashed line), DMPC nitrogen atom (dotted line).