Monolayer curvature stabilizes nanoscale raft domains in mixed lipid bilayers

Abstract

According to the lipid raft hypothesis, biological lipid membranes are laterally heterogeneous and filled with nanoscale ordered "raft" domains, which are believed to play an important role for the organization of proteins in membranes. However, the mechanisms stabilizing such small rafts are not clear, and even their existence is sometimes questioned. Here, we report the observation of raft-like structures in a coarse-grained molecular model for multicomponent lipid bilayers. On small scales, our membranes demix into a liquid ordered (lo) phase and a liquid disordered (ld) phase. On large scales, phase separation is suppressed and gives way to a microemulsion-type state that contains nanometer-sized lo domains in an ld environment. Furthermore, we introduce a mechanism that generates rafts of finite size by a coupling between monolayer curvature and local composition. We show that mismatch between the spontaneous curvatures of monolayers in the lo and ld phases induces elastic interactions, which reduce the line tension between the lo and ld phases and can stabilize raft domains with a characteristic size of the order of a few nanometers. Our findings suggest that rafts in multicomponent bilayers might be closely related to the modulated ripple phase in one-component bilayers.

Fig. 1.

Curvature mechanism generating rafts. The lo and ld regions in opposing monolayer leaflets are spatially correlated and have different spontaneous curvatures. This stabilizes domains of a finite size.

Fig. 2.

(A) Chemical potential difference in thermal energy units (k_BT) vs. cholesterol content from canonical simulations of small, mixed bilayer systems (162 lipids). The corresponding snapshots show the system in the ld state (B) and in the lo state (C). The darker chains represent C lipids.

Fig. 3.

Snapshots of a large bilayer system (20,000 lipids) featuring raft-like lo domains: top view (A) and an enlarged section of a side view (B). Parameters are k_BT = 1.4, μ ≈ 6.6 k_bT. (C) Chemical potential difference vs. C content from semigrandcanonical simulations of large systems.

Fig. 4.

Characterization of raft domains. (A) Raft size distribution. The distribution of rafts with a given radius of gyration (r.o.g.) is shown. (Inset) Actual fraction of the raft area found in rafts of a given size. Lines are guides for the eye; μ is given in units of k_BT. (B) Cross-correlation K_i of configuration i vs. percentile of conformations with randomly displaced monolayers, which have a higher correlation or anticorrelation . Every point corresponds to an independent simulation configuration i. The more skewed a distribution is to the right side, the greater is the mean (positive) correlation between rafts on both sides. The lower the percentile of a point, the less likely it is that this particular value is coincidental. a.u., arbitrary units.

Fig. 5.

Radially averaged structure factor of the raft conformations for different values of μ, with μ given in units of k_BT. a.u., arbitrary units.

Fig. 6.

Rescaled elastic contribution to the line tension λ_el(D) for disk-shaped rafts of diameter D (A) and stripe-shaped rafts of thickness D vs. D (B) in units of in-plane correlation length ξ and membrane parameter b.