Comparison of Ternary Bilayer Mixtures with Asymmetric or Symmetric Unsaturated Phosphatidylcholine Lipids by Coarse Grained Molecular Dynamics Simulations

Abstract

We studied the phase behavior of various ternary bilayer mixtures composed of cholesterol, an unsaturated lipid, and a fully saturated lipid, by means of molecular dynamics simulations of the MARTINI coarse grain model. We aimed at comparing lateral organization and local properties of bilayers containing phosphatidylcholine (PC) lipids, either with two unsaturated tails (symmetric), or one unsaturated and one saturated tail (asymmetric), as the low-melting component of the mixture. The number of unsaturations per chain was systematically varied in both classes of unsaturated lipids, to account for its consequences in segregation. In the asymmetric unsaturated PCs, the saturated tail was kept identical to the hydrophobic chains of the fully saturated lipid component. Membranes with a symmetric or an asymmetric unsaturated lipid, with the same kind of unsaturated chain, show different phase behavior. Symmetric polyunsaturated PCs set the separation in two phases. Instead, the asymmetric polyunsaturated lipids induced nonideal mixing of components in single-phase bilayers. A significative drop of temperature, within the accessible temperature range, enhances the segregation in mixtures with the more unsaturated asymmetric PC, but still within a single phase. This different phase behavior between membranes with symmetric and asymmetric unsaturated PCs is also observed for lipids with the same total number of unsaturations. On the other hand, the degree of unsaturation per se enhances the segregation, by increasing the composition fluctuations in single-phase membranes with asymmetric PC lipids, and raising the line tension in the two-phase bilayer mixtures with symmetric polyunsaturated PCs. Dynamic clusters of unsaturated asymmetric lipids can be identified. The clusters show no correlation between leaflets, as observed for the phase domains in mixtures with the symmetric polyunsaturated PCs. Interestingly, we found that asymmetric PC lipids have a preferential orientation such that their saturated tails increase their density toward the periphery of the clusters, facing regions enriched in the fully saturated lipids and cholesterol. The degree of unsaturation increases the cluster size and also enhances the anisotropy of the orientation. The surface density of cholesterol follows a gradient that favors its interaction with the saturated tails. Such gradients in composition lead to gradients in order parameters, such as the conformational order and the area of the tails, which increases away from the unsaturated lipid clusters. We compared, in addition, differences in hydrophobic length mismatch between acyl chains of the low-melting and high-melting components, in mixtures containing either symmetric or asymmetric unsaturated lipids.

Multiscale Modeling of Four-Component Lipid Mixtures: Domain Composition, Size, Alignment, and Properties of the Phase Interface

“…We note here that at low ρ in these simulations, and in ternary mixture simulations of DPPC/PUPC/chol, 52,53 small clusters reveal non-ideal mixing (see e.g. web enhanced object Movie_ρTrajectoryPhaseSeparation.mpg) rather than nanoscopic phase domains.…”

“…This is in agreement with previous Martini studies showing that more unsaturation of the low-Tm lipid enhances demixing. 52 An increase in lipid and monolayer thickness mismatch between the Lo and Ld phases as ρ increases (Figures S14 and S15A) may further drive intraleaflet phase separation 53,63–65 as a way to minimize the amount of unfavorable conformational adjustments and interactions at the interface.…”

Model parameters for simulation of physiological lipids

“…Lipid membranes are a popular choice for coarse graining because of the size of the fully solvated system and the slow lateral diffusion of its components . In an explicit lipid bilayer model, two‐tailed phospholipids interact via a CG description of head and tail functional groups, each of which are connected by flexible virtual bonds .…”

“…[4][5][6][7] Lipid membranes are a popular choice for coarse graining because of the size of the fully solvated system and the slow lateral diffusion of its components. [8][9][10][11] In an explicit lipid bilayer model, two-tailed phospholipids interact via a CG description of head and tail functional groups, each of which are connected by flexible virtual bonds. [12,13] The overall effect of the surrounding water can be captured implicitly [13][14][15][16][17] in the set of lipid and protein nonbond interaction potentials, assuming the parameterization is self-consistent.…”

Multiscale molecular modeling of tertiary supported lipid bilayers

“…Despite tremendous development of experimental work with SLBs, the influence of hard surfaces on the phase behavior and energy landscape of multi-component membranes, and the water layer in between them, is still not fully understood. Coarse-grained Molecular Dynamics (MD) 5 has been effective in studying a wide variety of multi-component free lipid bilayer (FLB) systems 6,7 . Only few studies have focused on SLBs with at most two components 8,9 .…”