Effect of lipid peroxidation on the properties of lipid bilayers: a molecular dynamics study

Abstract

Lipid peroxidation plays an important role in cell membrane damage. We investigated the effect of lipid peroxidation on the properties of 1-palmitoyl-2-linoleoyl-sn-glycero-3-phosphatidylcholine (PLPC) lipid bilayers using molecular dynamics simulations. We focused on four main oxidation products of linoleic acid with either a hydroperoxide or an aldehyde group: 9-trans, cis-hydroperoxide linoleic acid, 13-trans, cis-hydroperoxide linoleic acid, 9-oxo-nonanoic acid, and 12-oxo-9-dodecenoic acid. These oxidized chains replaced the sn-2 linoleate chain. The properties of PLPC lipid bilayers were characterized as a function of the concentration of oxidized lipids, with concentrations from 2.8% to 50% for each oxidation product. The introduction of oxidized functional groups in the lipid tail leads to an important conformational change in the lipids: the oxidized tails bend toward the water phase and the oxygen atoms form hydrogen bonds with water and the polar lipid headgroup. This conformational change leads to an increase in the average area per lipid and, correspondingly, to a decrease of the bilayer thickness and the deuterium order parameters for the lipid tails, especially evident at high concentrations of oxidized lipid. Water defects are observed in the bilayers more frequently as the concentration of the oxidized lipids is increased. The changes in the structural properties of the bilayer and the water permeability are associated with the tendency of the oxidized lipid tails to bend toward the water interface. Our results suggest that one mechanism of cell membrane damage is the increase in membrane permeability due to the presence of oxidized lipids.

FIGURE 1

Products of the oxidation of linoleic acid considered for this work.

FIGURE 2

Lipid fragments used for the calculation of bonded parameters and partial charges for the oxidized lipid tails.

FIGURE 3

Snapshots of a single PLPC and 13-tc taken at 5 ns intervals. Lipids are colored by atom type: nitrogen is blue, carbon is cyan, oxygen is red, and phosphorus is tan. Molecules are oriented along the z axis and superimposition was done on the phosphorus and oxygen atoms.

FIGURE 4

Electron density profiles for the oxygen atoms of the oxidized acyl chains and the phosphorus atoms of the headgroup in PLPC bilayers containing 11.1% of oxidized lipids.

FIGURE 5

(A) Total electron density in simulations of PLPC bilayers including two oxidation products, 12-al and 9-tc, at 50% concentration. (B) Relative electron density in x-ray diffraction experiments on DLPC and peroxidized products (reproduced from (22)).

FIGURE 6

The thickness and area per lipid of lipid bilayer, containing various concentrations of each oxidized lipid. Statistical error estimates are less than the size of the symbols for all the simulations (see Table 5), and are therefore omitted for the sake of clarity.

FIGURE 7

(A) Deuterium order parameter in the sn-2 lipid chains of PLPC and each oxidized lipid, in the simulations with 11% oxidized lipids. (B) Deuterium order parameter of the sn-1 chain of PLPC in the presence of 9-tc and (C) 9-al at different concentrations of oxidized lipid. Error bars were omitted in panels B and C, for the sake of clarity.

FIGURE 8

Average long time (D₂) lateral diffusion coefficients of PLPC and oxidized lipids as a function of the concentration of oxidized lipids.

FIGURE 9

Snapshot showing a stable water defect in a PLPC bilayer containing 50% 13-tc lipids. PLPC is shown as sticks in gray, 13-tc in cyan; all phosphate atoms are shown as tan spheres, oxygen atoms in the hydroperoxide group as red spheres, and water oxygen atoms are shown as blue spheres (with bigger size inside the bilayer).

FIGURE 10

Potential of mean force for water as a function of the distance from the center of the bilayer, in a bilayer containing pure PLPC or 11.1% oxidized lipids or 50% oxidized lipids. Error bars are omitted for clarity.