Effect of monovalent salt on cationic lipid membranes as revealed by molecular dynamics simulations

An atomic-scale understanding of cationic lipid membranes is required for development of gene delivery agents based on cationic liposomes. To address this problem, we recently performed molecular dynamics (MD) simulations of mixed lipid membranes comprised of cationic dimyristoyltrimethylammonium propane (DMTAP) and zwitterionic dimyristoylphosphatidylcholine (DMPC) (Biophys. J. 2004, 86, 3461-3472). Given that salt ions are always present under physiological conditions, here we focus on the effects of monovalent salt (NaCl) on cationic (DMPC/DMTAP) membranes. Using atomistic MD simulations, we found that salt-induced changes in membranes depend strongly on their composition. When the DMTAP mole fraction is small (around 6%), the addition of monovalent salt leads to a considerable compression of the membrane and to a concurrent enhancement of the ordering of lipid acyl chains. That is accompanied by reorientation of phosphatidylcholine headgroups in the outward normal direction and slight changes in electrostatic properties. We attribute these changes to complexation of DMPC lipids with Na+ ions which penetrate deep into the membrane and bind to the carbonyl region of the DMPC lipids. In contrast, at medium and high molar fractions of cationic DMTAP (50 and 75%) a substantial positive surface charge density of the membranes prevents the binding of Na+ ions, making such membranes almost insensitive to monovalent salt. Finally, we compare our results to the Poisson-Boltzmann theory. With the exception of the immediate vicinity of the bilayer plane, we found excellent agreement with the theory. This is as expected since unlike in the theoretical description the surface is now structured due to its atomic scale nature