The molecular face of lipid rafts in model membranes - PubMed (original) (raw)

The molecular face of lipid rafts in model membranes

H Jelger Risselada et al. Proc Natl Acad Sci U S A. 2008.

Abstract

Cell membranes contain a large number of different lipid species. Such a multicomponent mixture exhibits a complex phase behavior with regions of structural and compositional heterogeneity. Especially domains formed in ternary mixtures, composed of saturated and unsaturated lipids together with cholesterol, have received a lot of attention as they may resemble raft formation in real cells. Here we apply a simulation model to assess the molecular nature of these domains at the nanoscale, information that has thus far eluded experimental determination. We are able to show the spontaneous separation of a saturated phosphatidylcholine (PC)/unsaturated PC/cholesterol mixture into a liquid-ordered and a liquid-disordered phase with structural and dynamic properties closely matching experimental data. The near-atomic resolution of the simulations reveals remarkable features of both domains and the boundary domain interface. Furthermore, we predict the existence of a small surface tension between the monolayer leaflets that drives registration of the domains. At the level of molecular detail, raft-like lipid mixtures show a surprising face with possible implications for many cell membrane processes.

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Conflict of interest statement

The authors declare no conflict of interest.

Figures

Fig. 1.

Fig. 1.

Formation of Lo domains in ternary lipid mixtures. (A) Color coding of the lipid components. Green is used for the saturated lipids, and red is used for the polyunsaturated lipids. Cholesterol is depicted in gray with a white hydroxyl group. (B) Time-resolved phase segregation of a planar membrane viewed from above, starting from a randomized mixture (t = 0), ending with the Lo/Ld coexistence (t = 20 μs). (C) Phase segregation for the same lipid mixture in a small, 20-nm-diameter liposome. Initial (t = 0) and final (t = 4 μs, both top view and cut through the middle) configuration. (D and E) Multiple periodic images (2 × 2) of the phase-separated diC16-PC/diC18:2-PC/cholesterol systems show striped pattern formation in the 0.42:0.28:0.3 system (D) and circular domains in the 0.28:0.42:0.3 system (E). (Scale bar: 5 nm.)

Fig. 2.

Fig. 2.

Structural and dynamic properties of the 2 domains. (A) Side view of the planar diC16-PC/diC18:2-PC/cholesterol 0.42:0.28:0.3 system at the end of the simulation, revealing the molecular organization in both the Lo and Ld phases. The white arrow points to a cholesterol oriented in between the monolayer leaflets. (B–D) Various properties of the membrane along the direction perpendicular to the phase boundaries. The Lo phase is centered, flanked by 2 periodic halves of the Ld domain. A transition zone separating the 2 phases is tentatively indicated by dashed, black lines. Green, red, and gray are used to distinguish properties of diC16-PC, diC18:2-PC, and cholesterol. (B) Composition of the membrane expressed as a mole fraction of each of the 3 components. Thin lines represent the 2 monolayers separately; the thicker line represents the average. (C) Average tail order parameter for PC lipids (left axis) and membrane thickness (black curve, right axis). (D) Lipid lateral diffusion rate (left axis) and cholesterol flip-flop rate (black curve, right axis).

Fig. 3.

Fig. 3.

Lateral organization of cholesterol in the Lo phase. (A) Top view of the planar membrane illustrating the typical instantaneous cholesterol organization across the raft-like phase and the boundary zone. The green and red backgrounds represent the positions of the saturated and unsaturated lipids. (B) Cholesterol–cholesterol radial distribution function with a solvent-separated peak at a distance of 1 nm (arrow). Results obtained from the current study are displayed by the solid line; results based on all-atom simulations (13) are shown by the dashed line for comparison. (Inset) Frequency distribution of cholesterol cluster sizes obtained from the simulation (solid bars) compared to a random distribution (open bars).

Fig. 4.

Fig. 4.

Driving forces for domain formation. (A) Image showing the overlap of the 2 raft domains at the end of the simulation (t = 20 μs). Only the CG beads corresponding to the phosphate group (PCs) or hydroxyl group (cholesterol) are shown as green solid spheres for the lower monolayer and transparent yellow spheres for the upper monolayer. The direction across the domains is indicated by x, and the direction along the domains is indicated by y. (B) Overlaying instantaneous configurations of the domain interfaces in the upper (yellow) and lower (green) monolayer leaflets during the last 4 μs of the simulation. Note the difference in fluctuations for the 2 innermost interfaces, which oppose the Lo phase, vs. the outermost interfaces opposing the Ld domain. (C) Minimization of the perimeter of the domain interface for each of the 2 monolayers (yellow and green curves, left axis) and the increase in registration between the domains formed in both monolayer leaflets, expressed as the surface overlap fraction (black curve, right axis). (D) Logarithmic probability of the area mismatch vs. area mismatch. The solid line denotes a linear fit of the data in the high mismatch regime, from which the effective surface tension between the monolayer leaflets is estimated.

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