Interplay of unsaturated phospholipids and cholesterol in membranes: effect of the double-bond position

Abstract

The structural and dynamical properties of lipid membranes rich in phospholipids and cholesterol are known to be strongly affected by the unsaturation of lipid acyl chains. We show that not only unsaturation but also the position of a double bond has a pronounced effect on membrane properties. We consider how cholesterol interacts with phosphatidylcholines comprising two 18-carbon long monounsaturated acyl chains, where the position of the double bond is varied systematically along the acyl chains. Atomistic molecular dynamics simulations indicate that when the double bond is not in contact with the cholesterol ring, and especially with the C18 group on its rough beta-side, the membrane properties are closest to those of the saturated bilayer. However, any interaction between the double bond and the ring promotes membrane disorder and fluidity. Maximal disorder is found when the double bond is located in the middle of a lipid acyl chain, the case most commonly found in monounsaturated acyl chains of phospholipids. The results suggest a cholesterol-mediated lipid selection mechanism in eukaryotic cell membranes. With saturated lipids, cholesterol promotes the formation of highly ordered raft-like membrane domains, whereas domains rich in unsaturated lipids with a double bond in the middle remain highly fluid despite the presence of cholesterol.

FIGURE 1

(a) Molecular structures of DSPC molecules with numbering of atoms and torsion angles (T). The unsaturated bonds in the other studied species are marked and numbered in the sn-1 chain. (b) Numbering of atoms for cholesterol. In both panels, the chemical symbol for carbon atoms, C, is omitted.

FIGURE 2

(a) Average surface area per PC. (b) Average z-distance between phosphorous atoms in opposite leaflets. (c) Average z-distance between cholesterol oxygens in opposite layers. All results are shown as a function of the double-bond position. Solid lines correspond to the systems with cholesterol, whereas dashed curves stand for the pure single-component bilayers (17).

FIGURE 3

Comparison of the electron density profiles of the DOPC/Chol bilayer (thin) and pure DOPC bilayer (thick). In both cases, system (solid), PC (dashed), water (dotted), and cholesterol (dot-dashed) electron density profiles are plotted.

FIGURE 4

Deuterium order parameter (S_CD) profiles of the sn-2 chains for (a) PC/Chol bilayers and (b) pure PC bilayers. 18:0PC (thick solid), 18:1c3PC (dot-dashed), 18:1c5PC (dotted), DOPC (solid), and 18:1c13PC (dashed).

FIGURE 5

(a) Average values of the S_CD order parameter as a function of the double-bond position for both sn-1 (dashed) and sn-2 (solid) chains in the systems with and without cholesterol. The results for the tail of cholesterol are also shown (dotted). (b) Average tilt angle as a function of the position of the double bond for both sn-1 (dashed) and sn-2 (solid) chains in the systems with and without cholesterol. The tilt results for the cholesterol ring system are also provided (dotted). (c) Gauche number as a function of the unsaturation position for both sn-1 (dashed) and sn-2 (solid) chains in the systems with and without cholesterol. The curves with circle symbols correspond to the pure systems. Stars indicate fully saturated systems.

FIGURE 6

(a) Average number of hydrogen bonds with water per PC as a function of the double-bond position. (b) Average number of charge pairs involving two PC molecules (PC/PC) as a function of the unsaturation position. In both panels the solid line stands for mixed PC/Chol bilayers and the dashed line corresponds to pure PC bilayers.

FIGURE 7

Three-dimensional RDF of the double-bond center of mass around cholesterol C18 (a) and C19 (b) methyl groups in the sn-2 chains. The behavior of sn-1 is equivalent (not shown). 18:1c3PC (dot-dashed), 18:1c5PC (dotted), DOPC (solid), and 18:1c13PC (dashed).

FIGURE 8

Values at 0.48 nm (I_0.48) of the three-dimensional RDFs of the double-bond center of mass around (a) cholesterol C18 and (b) C19 methyl groups for sn-1 (dashed) and sn-2 (solid) chains as a function of the double-bond position.