Abstract
Biological membranes are composed of lipid bilayers that are often asymmetric with regards to the lipid composition and/or aqueous solvent they separate. Studying lipid asymmetry both experimentally and computationally is challenging. Molecular dynamics simulations of lipid bilayers with asymmetry are difficult due to finite system sizes and time scales accessible to simulations. Due to the very slow flip-flop rate for phospholipids, one must first choose how many lipids are on each side of the bilayer, but the resulting bilayer may be unstable (or metastable) due to differing tensile and compressive forces between leaflets. Here we use molecular dynamics simulations to investigate a number of different asymmetric membrane systems, both with atomistic and coarse-grained models. Asymmetries studied include differences in number of lipids, lipid composition (unsaturated and saturated tails and different headgroups), and chemical gradients between the aqueous phases. Extensive analysis of the bilayers’ properties such as area per lipid, density, and lateral pressure profiles are used to characterize bilayer asymmetry. We also address how cholesterol (which flip-flops relatively quickly) influences membrane asymmetries. Our results show how each leaflet is influenced by the other and can mitigate the structural changes to the bilayer overall structure. Cholesterol can respond to changes in bilayer asymmetry to alleviate some of the effect on the bilayer structure, but that will alter its leaflet distribution, which in turn affects its chemical potential. Ionic imbalances are shown to have a modest change in bilayer structure, despite large changes in the electrostatic potential. Bilayer asymmetry can also induce a modest electrostatic potential across the membrane. Our results highlight the importance of membrane asymmetry on bilayer properties, the influence of lipid headgroups, tails and cholesterol on asymmetry, and the ability of lipids to adapt to different environments.
Highlights
Lipid membranes separate organelles and cells from their exterior environments
To determine what the number asymmetry should be, we systematically reduced the number of lipids in the lower leaflet, simulating 4–5 repeats at each asymmetry value ranging from 0 to 35 random lipids removed from the lower leaflet
Our results suggest that for the systems tested here this is true for some properties, such as the overall membrane density and area per lipid (APL), cholesterol can increase the effect on some other properties, such as the lateral pressure profile (LPP)
Summary
Lipids can spontaneously assemble into a bilayer, which is the basic structure of cell membranes. These lipid bilayers function as a selective barrier to molecular entry/exit for the cell and serve as planar platforms for colocalizing various cell machinery. Because of their small scale, complexity and fluid phase behavior, it is difficult to study lipid bilayers directly, in vivo. It has been long established that most cellular membranes have an asymmetric distribution of lipids between the inner and outer bilayer leaflets. Quantifying lipid compositions in either leaflet, transleaflet exchange (flipflop), how cells create and maintain asymmetry, and the biological and physical effects of membrane asymmetry remain open research areas
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