Long chain sphingomyelin depletes cholesterol from the cytoplasmic leaflet in asymmetric lipid membranes.

The transbilayer distribution of cholesterol (CHL) in complex asymmetric lipid membranes remains controversial, with contrasting investigations suggesting that there is more CHL either in the exoplasmic, outer leaflet (OL) or the cytoplasmic, inner leaflet (IL) depending on cell type or model, membrane composition, and method of investigation. Here, we launch systematic coarse-grained molecular dynamics simulations to investigate the impact of the sphingomyelin (SM) acyl chain length upon CHL distribution in asymmetric lipid membrane mixtures which account for the variation of the most abundant headgroups and acyl chain unsaturation in the two membrane leaflets. We find that there is always more CHL in the OL, but longer chain SM depletes more CHL from the IL than short chain SM in simple membrane mixtures containing SM and 16 : 0, 18 : 1 phospholipids. The difference between longer and shorter chain SM is neutralised in a more complex asymmetric membrane, where there are more saturated tails in the outer leaflet. We propose that interdigitation of long-chain SM into the opposing IL pushes cytoplasmic CHL towards the OL, but higher chain saturation of the outer leaflet compensates for the effect of SM chain length.

Faster Simulations with a 5 fs Time Step for Lipids in the CHARMM Force Field.

The performance of all-atom molecular dynamics simulations is limited by an integration time step of 2 fs, which is needed to resolve the fastest degrees of freedom in the system, namely, the vibration of bonds and angles involving hydrogen atoms. The virtual interaction sites (VIS) method replaces hydrogen atoms by massless virtual interaction sites to eliminate these degrees of freedom while keeping intact nonbonded interactions and the explicit treatment of hydrogen atoms. We have modified the existing VIS algorithm for most lipids in the popular CHARMM36 force field by increasing the hydrogen atom masses at regular intervals in the lipid acyl chains and obtained lipid properties and pore formation free energies in very good agreement with those calculated in simulations without VIS. Our modified VIS scheme enables a 5 fs time step resulting in a significant performance gain for all-atom simulations of membranes. The method has the potential to make longer time and length scales accessible in all-atom simulations of membrane-protein complexes.

Membrane Tubulation in Lipid Vesicles Triggered by the Local Application of Calcium Ions.

Experimental and theoretical studies on ion-lipid interactions predict that binding of calcium ions to cell membranes leads to macroscopic mechanical effects and membrane remodeling. Herein, we provide experimental evidence that a point source of Ca2+ acting upon a negatively charged membrane generates spontaneous curvature and triggers the formation of tubular protrusions that point away from the ion source. This behavior is rationalized by strong binding of the divalent cations to the surface of the charged bilayer, which effectively neutralizes the surface charge density of outer leaflet of the bilayer. The mismatch in the surface charge density of the two leaflets leads to nonzero spontaneous curvature. We probe this mismatch through the use of molecular dynamics simulations and validate that calcium ion binding to a lipid membrane is sufficient to generate inward spontaneous curvature, bending the membrane. Additionally, we demonstrate that the formed tubular protrusions can be translated along the vesicle surface in a controlled manner by repositioning the site of localized Ca2+ exposure. The findings demonstrate lipid membrane remodeling in response to local chemical gradients and offer potential insights into the cell membrane behavior under conditions of varying calcium ion concentrations.

Quantifying the Relationship between Curvature and Electric Potential in Lipid Bilayers.

Cellular membranes mediate vital cellular processes by being subject to curvature and transmembrane electrical potentials. Here we build upon the existing theory for flexoelectricity in liquid crystals to quantify the coupling between lipid bilayer curvature and membrane potentials. Using molecular dynamics simulations, we show that headgroup dipole moments, the lateral pressure profile across the bilayer, and spontaneous curvature all systematically change with increasing membrane potentials. In particular, there is a linear dependence between the bending moment (the product of bending rigidity and spontaneous curvature) and the applied membrane potentials. We show that biologically relevant membrane potentials can induce biologically relevant curvatures corresponding to radii of around 500 nm. The implications of flexoelectricity in lipid bilayers are thus likely to be of considerable consequence both in biology and in model lipid bilayer systems.