University of Groningen Partitioning of Lipids at Domain Boundaries in Model Membranes

Line-active molecules (‘‘linactants’’) that bind to the boundary interface between different fluid lipid domains in membranes have a strong potential as regulators of the lateral heterogeneity that is important for many biological processes. Here, we use molecular dynamics simulations in combination with a coarse-grain model that retains near-atomic resolution to identify lipid species that can act as linactants in a model membrane that is segregated into two lipid domains of different fluidity. Our simulations predict that certain hybrid saturated/unsaturated chain lipids can bind to the interface and lower the line tension, whereas cone-shaped lysolipids have a less pronounced effect. Received for publication 29 July 2010 and in final form 26 August 2010. *Correspondence: [email protected] or [email protected] This is an Open Access article distributed under the terms of the Creative Commons-Attribution Noncommercial License (http://creativecommons.org/licenses/by-nc/2.0/), which permits unrestricted noncommercial use, distribution, and reproduction in any medium, provided the original work is properly cited. The lateral heterogeneity of biological membranes has important implications for the function of cells (1). Nevertheless, to study the organization of biological membranes remains a challenge, because it is inherently difficult to characterize fluctuating lipid assemblies in the membranes of living cells (2). Model membranes (3–6) and isolated plasma membranes (7–9) are more frequently studied, because large-scale phase separation can occur in these systems. In particular, ternary mixtures of saturated lipids, unsaturated lipids, and cholesterol can segregate into two coexisting fluid lipid domains, a liquid-ordered (Lo) and liquid-disordered (Ld) phase. Such domains have been widely studied, because they may be closely linked to lipid nanodomains in cell membranes (10). It is intriguing to devise molecules that specifically bind at the boundary interface between the different lipid domains, thereby modifying the boundary properties while leaving the bulk regions unaltered (11). As they are supposed to reduce the line tension (or energetic cost) of the one-dimensional boundary interface, such molecules can be called linactants, analogous to surfactants (which modify the surface tension at an oil/water interface). Possible line-active molecules could be, e.g., certain lipids, or lipid-anchored or transmembrane proteins. In this work, our aim is to identify lipid species that can act as biological linactants. To that end, we inserted potentially line-active lipids into a lipid bilayer that consists of two coexisting fluid domains and studied their partitioning at the domain boundary during extensive coarse-grain (CG) molecular dynamics (MD) simulations. Two different types of lipids were chosen as potential candidates, hybrid saturated/unsaturated chain lipids, and a single-chain lysolipid. These different species were chosen to investigate two possible mechanisms: hybrid lipids might accumulate at the domain boundary due to their mixed hydrocarbon chains, whereas lysolipids are cone-shaped and may thus be attracted due to the (local) curvature at the domain boundary, which arises from the thickness mismatch between the domains (~0.7 nm in our bilayer). Fig. 1 shows the lipid bilayer studied, a ternary mixture of saturated diC16:0PC (dipalmitoyl-phosphatidylcholine, DPPC), doubly unsaturated diC18:2PC (dilinoleoyl-PC, DLiPC), and cholesterol (molar ratio 0.42:0.28:0.3). In a recent CG-MD study from our group, it was shown that this bilayer spontaneously segregates into two fluid domains at 295 K (12). DLiPC enhances the driving force for phase separation (13), while yielding domain properties similar to those observed in DOPC/DPPC/cholesterol bilayers (4). The liquid-ordered (Lo) domain mainly consists of DPPC and cholesterol, whereas the liquid-disordered (Ld) domain is enriched in DLiPC and contains less cholesterol. The domains are separated by a boundary interface that is ~5 nm in width (14). Here, we added small amounts (40 molecules, 2 mol %) of the fourth component to this ternary mixture. The idea was to introduce enough molecules to obtain proper statistics during the MD simulations, while perturbing the phase diagram of the ternary system as weakly as possible. As hybrid lipids, C16:0C18:1PC (palmitoyl-oleoyl-PC, POPC) and C16:0C18:2PC (palmitoyl-linoleoyl-PC, PLiPC) were added; single-chain C16:0PC (palmitoyl-PC, LysoPC) was chosen as a cone-shaped lipid. Editor: Scott Feller. 2010 by the Biophysical Society doi: 10.1016/j.bpj.2010.08.072 Biophysical Journal Volume 99 December 2010 L91–L93 L91