Lipid Clustering Correlates with Membrane Curvature as Revealed by Molecular Simulations of Complex Lipid Bilayers

Cell membranes are complex multicomponent systems, which are highly heterogeneous in the lipid distribution and composition. To date, most molecular simulations have focussed on relatively simple lipid compositions, helping to inform our understanding of in vitro experimental studies. Here we describe on simulations of complex asymmetric plasma membrane model, which contains seven different lipids species including the glycolipid GM3 in the outer leaflet and the anionic lipid, phosphatidylinositol 4,5-bisphophate (PIP2), in the inner leaflet. Plasma membrane models consisting of 1500 lipids and resembling the in vivo composition were constructed and simulations were run for 5 µs. In these simulations the most striking feature was the formation of nano-clusters of GM3 within the outer leaflet. In simulations of protein interactions within a plasma membrane model, GM3, PIP2, and cholesterol all formed favorable interactions with the model α-helical protein. A larger scale simulation of a model plasma membrane containing 6000 lipid molecules revealed correlations between curvature of the bilayer surface and clustering of lipid molecules. In particular, the concave (when viewed from the extracellular side) regions of the bilayer surface were locally enriched in GM3. In summary, these simulations explore the nanoscale dynamics of model bilayers which mimic the in vivo lipid composition of mammalian plasma membranes, revealing emergent nanoscale membrane organization which may be coupled both to fluctuations in local membrane geometry and to interactions with proteins.Author Summary: Cell membranes play important roles in vivo both in shielding the cell interior from the surrounding environment and in cell function through lipid components of the membrane having roles in controlling protein function, cell signaling etc. We employ molecular dynamics simulations to explore the behavior of biologically realistic membrane models. Our simulations reveal nano-domain clustering of the glycolipid GM3 and to a lesser extent of the anionic lipid phosphatidylinositol 4,5-bisphophate (PIP2). When including transmembrane proteins we are able to observe preferential interactions of known regulatory lipids (e.g. GM3, PIP2 and cholesterol) with the proteins. Membrane curvature is shown to be coupled to the local lipid composition, suggestive of a link between lipid nano-domains and membrane geometry.