Molecular dynamics simulations of a complex plasma membrane reveal finely-tuned sphingolipid hydrogen bonds

Abstract

The study of lipid bilayers has lagged behind that of other complex molecular assemblies due to the dynamic nature of lipid bilayers and the paucity of experimental techniques to study them in atomic detail. This is particularly true when analyzing interactions between lipid components of membranes. We now report a multi-resolution in silico analysis of a lipid bilayer based on the asymmetric lipid composition of the human erythrocyte plasma membrane. Our approach combines a coarse-grained bilayer simulation with resolution transformation to multiple smaller all-atom simulations. The coarse-grained simulation was consistent with previously published studies, as demonstrated by analysis of cholesterol translocation and neighbor enrichment. Subsequently, small patches from the coarse-grained simulations were transformed to all-atom resolution; quality control analysis of this data was again consistent with area per lipid and chain orientational order measurements of model bilayers. All-atom simulations permitted us to examine intermolecular and intramolecular hydrogen-bonding with a particular focus on sphingolipids, which unlike glycerophospholipids, donate hydrogen bonds in the bilayer interface region. We determined the relative contribution of each donor and acceptor hydrogen bond in lipid-lipid interactions and took advantage of atomic level resolution to study hydrogen-bonding for d-erythro-, 3-keto-, phyto- and dihydro-sphingolipids. Removing one of the hydrogen bond donors in sphingomyelin (SM) (by modeling 3-keto-SM rather than d-erythro-SM) resulted in an unexpected compensatory increase in hydrogen bond donation by the amide proton to neighboring SM. Phyto-SM increased hydrogen-bonding by the 3-position hydroxyl, while dihydro-SM reduced donation to cholesterol. Our results not only illustrate the usefulness of all-atom simulations to reveal membrane interactions less accessible by other methods, but also strengthen our recent suggestions that lipid bilayers are finely-tuned molecular assemblies in which atomic interactions play critical roles in maintaining and regulating membrane structure and function.