The Membrane Dipole\nPotential and the Roles of Interfacial\nWater and Lipid Hydrocarbon Chains

Understanding membrane charge transport processes, including\nthe\nactions of ion channels, pumps, carriers, and membrane-active peptides,\nrequires a description of the electrostatics of the lipid bilayer.\nWe have simulated a library of different lipid chemistries to reveal\nthe impact of the headgroup, glycerol backbone, and hydrocarbon chains\non the membrane dipole potential. We found a strong dependence of\nthe potential on lipid packing, but this was not caused by the packing\nof lipid polar components, due to cancellation of their electric fields\nby electrolyte. In contrast, lipid tail contributions were determined\nby area per lipid, arising from two countering effects. Increased\narea per lipid leads to chain tilting that increases methylene dipole\nprojections to strengthen the electric field within the bilayer, while\nat the same time decreasing the electric field from terminal methyl\ngroups. Moreover, electric fields from some nonterminal groups and\nthe terminal methyl group can extend beyond the bilayer center and\nbe canceled by the opposing leaflet. This interleaflet field annulment\nexplains the experimental reduction in dipole potential for unsaturated\nand branched lipid bilayers, by as much as ∼200 mV, as well\nas experiments that substitute chain carbons with sulfur. Replacing\nester with ether groups (eliminating two carbonyl groups) causes a\nsignificant reduction in potential, also by ∼200 mV, in agreement\nwith experiment. We show that the effect can be largely attributed\nto the loss of aligned water molecules in the glycerol backbone region,\nlowering the potential inside the bilayer core. When only one of the\ntwo carbonyls is removed (using a hybrid ester-ether lipid or a single-chain\nlipid), most of this reduction in potential was lost, with the single\ncarbonyl group able to maintain full hydration in the interfacial\nregion. While headgroup chemistry can have a major effect (by as much\nas ±100 mV relative to phosphatidylcholine), anionic headgroups\neither decrease or increase the dipole potential, with the variation\ninvolving perturbation in hydrogen-bonded water molecules and changes\nin packing of lipid tails. Overall, these results suggest that membrane\nelectrostatics are dominated by aligned water molecules at the polar–hydrocarbon\ninterface and, surprisingly, by the charge distribution of the nonpolar\nlipid tails, and not the packing of headgroup and glycerol carbonyl\ndipoles.