Molecular mechanisms of spontaneous curvature and softening in complex lipid bilayer mixtures.

Membrane reshaping is an essential biological process. The chemical composition of lipid membranes determines their mechanical properties and thus the energetics of their shape. Hundreds of distinct lipid species make up native bilayers, and this diversity complicates efforts to uncover what compositional factors drive membrane stability in cells. Simplifying assumptions, therefore, are used to generate quantitative predictions of bilayer dynamics based on lipid composition. One assumption commonly used is that "per lipid" mechanical properties are both additive and constant-that they are an intrinsic property of lipids independent of the surrounding composition. Related to this is the assumption that lipid bulkiness, or "shape," determines its curvature preference, independently of context. In this study, all-atom molecular dynamics simulations on three separate multilipid systems were used to explicitly test these assumptions, applying methodology recently developed to isolate properties of single lipids or nanometer-scale patches of lipids. The curvature preference experienced by populations of lipid conformations were inferred from their redistribution on a dynamically fluctuating bilayer. Representative populations were extracted by both structural similarity and semi-automated hidden Markov model analysis. The curvature preferences of lipid dimers were then determined and compared with an additive model that combines the monomer curvature preference of both the individual lipids. In all three systems, we identified conformational subpopulations of lipid dimers that showed non-additive curvature preference, in each case mediated by a special chemical interaction (e.g., hydrogen bonding). Our study highlights the importance of specific chemical interactions between lipids in multicomponent bilayers and the impact of interactions on bilayer stiffness. We identify two mechanisms of bilayer softening: diffusional softening, driven by the dynamic coupling between lipid distributions and membrane undulations, and conformational softening, driven by the inter-conversion between distinct dimeric conformations.

Spatial extent of a single lipid's influence on bilayer mechanics.

To what spatial extent does a single lipid affect the mechanical properties of the membrane that surrounds it? The lipid composition of a membrane determines its mechanical properties. The shapes available to the membrane depend on its compositional material properties, and therefore, the lipid environment. Because each individual lipid species' chemistry is different, it is important to know its range of influence on membrane mechanical properties. This is defined herein as the lipid's mechanical extent. Here, a lipid's mechanical extent is determined by quantifying lipid redistribution and the average curvature that lipid species experience on fluctuating membrane surfaces. A surprising finding is that, unlike unsaturated lipids, saturated lipids have a complicated, nonlocal effect on the surrounding surface, with the interaction strength maximal at a finite length-scale. The methodology provides the means to substantially enrich curvature-energy models of membrane structures, quantifying what was previously only conjecture.