Cholesterol induces uneven curvature of asymmetric lipid bilayers

Abstract

A remarkable flexibility is observed in biological membranes, which allows them to form the structures of different curvatures. We addressed the question of intrinsic ability of phospholipid membranes to form highly curved structures and the role of cholesterol in this process. The distribution of cholesterol in the highly curved asymmetric DOPC/DOPS lipid bilayer was investigated by the coarse-grained molecular dynamics simulations in the membrane patches with large aspect ratio. It is shown that cholesterol induces uneven membrane curvature promoting the formation of extended flattened regions of the membrane interleaved by sharp bends. It is shown that the affinity of cholesterol to anionic DOPS or neutral DOPC lipids is curvature dependent. The cholesterol prefers DOPS to DOPC in either planar or highly curved parts of the membrane. In contrast, in the narrow interval of moderate membrane curvatures this preference is inverted. Our data suggest that there is a complex self-consistent interplay between the membrane curvature and cholesterol distribution in the asymmetric lipid bilayers. The suggested new function of cholesterol may have a biological relevance.

Figure 1

Examples of highly curved membrane blebs formation in living cells during reticulocyte enucleation [10] (a) and during the mitosis of Drosophila S2 cell [11] (b).

Figure 2

The scheme of coarse graining used in MARTINI model [12, 13]. Coarse-grained particles are shown as semitransparent spheres and superimposed into the atomistic representations of the corresponding molecules. White rectangles indicate double bonds in the lipid tails. The figure is adapted from MARTINI web site http://md.chem.rug.nl/cgmartini/index.php/about/martini.

Figure 3

The shape of the model membrane with cholesterol. (a) Initial planar bilayer. (b) Final curved bilayer after 20 μs of simulation. The scales of the panels (a) and (b) are shown. DOPC lipids are black, DOPS lipids are gray, and cholesterol molecules are white and are shown in surface representation. Phosphate groups of the lipids are shown as large spheres. Vertical lines show the extents of the periodic simulation box in X dimension. The system without cholesterol looks very similar.

Figure 4

Visualization of the bilayer midline and the curvature at t = 20 μs in the simulation with cholesterol. The phosphate coarse grained particles of both monolayers are shown as small spheres. The membrane midline is shown as a solid black line. The radii of the gray spheres drawn on the midline are proportional to the absolute value of the membrane curvature in the given point. Vertical lines show the size of the periodic simulation box in X dimension.

Figure 5

Evolution of the mean bilayer curvature in MD simulations.

Figure 6

(a) Distributions of the membrane curvature in the simulation with and without cholesterol. (b) Free energy of transition from the equilibrium system without cholesterol to the equilibrium system with cholesterol as a function of the membrane curvature. Gray lines show hypothetical shape of the curve in the regions, which are not covered with data points. These lines are drawn for illustrative purposes in a qualitative manner and reflect the fact that the free energy profile must be limited by “walls” in order to insure the existence of steady states in the system.

Figure 7

(a) Distributions of the membrane curvature in the individual lipid domains containing either DOPC or DOPS lipids measured in the locations of cholesterol molecules. (b) Free energy of transferring single cholesterol molecule from the lipid domain containing DOPC lipids to the domain containing DOPS lipids as a function of the membrane curvature. Gray lines show hypothetical shape of the curve in the regions, which are not covered with data points (see Figure 6 for explanation).

Figure 8

Schematic representation of evenly (a) and unevenly (b) curved bilayer. In (a) the whole bilayer patch is bent with almost the same radius of curvature. In (b) there are regions with very different radii of curvature. In our simulations the system without cholesterol is closer to the case (a) while the addition of cholesterol induces uneven curvature similar to (b).