Lessons of slicing membranes: interplay of packing, free area, and lateral diffusion in phospholipid/cholesterol bilayers

Abstract

We employ 100-ns molecular dynamics simulations to study the influence of cholesterol on structural and dynamic properties of dipalmitoylphosphatidylcholine bilayers in the fluid phase. The effects of the cholesterol content on the bilayer structure are considered by varying the cholesterol concentration between 0 and 50%. We concentrate on the free area in the membrane and investigate quantities that are likely to be affected by changes in the free area and free volume properties. It is found that cholesterol has a strong impact on the free area properties of the bilayer. The changes in the amount of free area are shown to be intimately related to alterations in molecular packing, ordering of phospholipid tails, and behavior of compressibility moduli. Also the behavior of the lateral diffusion of both dipalmitoylphosphatidylcholine and cholesterol molecules with an increasing amount of cholesterol can in part be understood in terms of free area. Summarizing, our results highlight the central role of free area in comprehending the structural and dynamic properties of membranes containing cholesterol.

FIGURE 1

Structural formulae of DPPC and cholesterol molecules. The molecular masses of DPPC and cholesterol are 734.1 and 386.7 amu.

FIGURE 2

Temporal behavior of area per molecule. The curves correspond to (from top to bottom) cholesterol concentrations 0.0%, 4.7%, 12.5%, 20.3%, 29.7%, and 50.0%.

FIGURE 3

Order parameter profiles for (a) sn-1 and (b) sn-2 tails. The cholesterol concentrations are 0.0% (○), 4.7% (•), 12.5% (□), 20.3% (▪), 29.7% (⋄), and 50.0% (♦), and the index n increases toward the center of the bilayer.

FIGURE 4

Total electron density profiles as functions of distance z from bilayer center. The curves correspond to the various cholesterol concentrations as 0.0% (dash-dotted gray), 4.7% (solid black), 12.5% (solid gray), 20.3% (dashed black), 29.7% (dashed gray), and 50.0% (dash-dotted black).

FIGURE 5

Electron density profiles for molecular species and atomic groups: (a) DPPC, (b) cholesterol, (c) water, (d) DPPC tails (atoms 15–31 and 34–50), (e) phosphate groups, and (f) cholesterol ring system. The curves correspond to the cholesterol concentrations as indicated in Fig. 4. For reasons of clarity, the densities for the system with 50% cholesterol are not shown.

FIGURE 6

Average area per molecule as function of cholesterol concentration. The inset shows the average areas for DPPC (•) and cholesterol (○), i.e., and computed as in a recent simulation study by Hofsäß et al. (2003). The errors are smaller than the markers.

FIGURE 7

Areas per DPPC (•) and cholesterol (○), i.e., and computed using Voronoi tessellation. The errors for DPPC are smaller than the markers.

FIGURE 8

Cross sections of bilayer with 20.3% cholesterol at 100 ns. DPPC grid elements have been colored red, cholesterol is green, and water blue. The remaining area, i.e., the free area, is white. The panels correspond to slices at different distances z from the bilayer center: (a) bilayer center, (b) z ∼ 1 nm, (c) z ∼ 1.7 nm, (d) z ∼ 2 nm.

FIGURE 9

Area profiles for bilayer with 20.3% cholesterol scaled by total bilayer area: DPPC area profile 〈A_DPPC(z)〉/〈A_tot〉 (solid black); cholesterol area profile 〈A_chol(z)〉/〈A_tot〉 (solid gray); water area profile 〈A_water(z)〉/〈A_tot〉 (dashed black); and free area profile 〈A_free(z)〉/〈A_tot〉 (dashed gray). The errors of the scaled areas are of the order of a few percent.

FIGURE 10

Numbers of (a) DPPC and (b) cholesterol molecules as functions of distance from bilayer center. The curves correspond to the cholesterol concentrations as indicated in Fig. 4. The errors are of the order of <1%.

FIGURE 11

Cross-sectional close-packed areas for (a) DPPC and (b) cholesterol molecules as functions of distance from bilayer center. The curves correspond to the cholesterol concentrations as indicated in Fig. 4. The errors are of the order of a few percent. In the water phase, the relative errors for a_chol are somewhat larger.

FIGURE 12

Free areas per molecule as functions of distance from bilayer center for different cholesterol concentrations. The curves correspond to the cholesterol concentrations as indicated in Fig. 4.

FIGURE 13

Lateral diffusion coefficients of DPPC (•) and cholesterol (○) molecules as functions of cholesterol concentration.

FIGURE 14

Area compressibility moduli as functions of distance from bilayer center. The curves correspond to the cholesterol concentrations as indicated in Fig. 4. The errors are between 10 and 20%.

FIGURE 15

Order parameters versus close-packed areas for DPPC at 1 nm from bilayer center. The markers represent values computed from the simulations and the solid line is a fit to these data based on Eq. 7.