Effect of Monovalent Salt on Cationic Lipid Membranes As Revealed by Molecular Dynamics Simulations

Abstract

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 saltinduced 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.

Molecular electrometer and binding of cations to phospholipid bilayers

“…Consequently, values of m i are negative for bound positive charges; for Ca 2+ binding to POPC bilayer (in the presence of 100 mM NaCl), combination of atomic absorption spectra and 2 H NMR experiments gave m α = −20.5 and m β = −10.0 30 . This decrease can be rationalised by electrostatically induced tilting of the choline P-N dipole 31,32,46 -also seen in simulations 23,24,47,48 -and is in line with the order parameter increase related to the P-N vector tilting more parallel to the membrane plane seen with decreasing hydration levels 45 .…”

Ion Dynamics in Cationic Lipid Bilayer Systems in Saline Solutions

“…At low TAP (6%), Na + binds to the negatively charged carbonyl region, but at higher TAP (50% and especially 75%), Na + populates only the intermembrane water layer. 61 These qualitatively different spatial distributions of Na + and Cl -correspond to qualitatively different dynamics, as is illustrated in Figure 4 for two different DMTAP molar fractions (6 and 75%). Separation of time scales between Na + release from the carbonyl region (.10 ns) and ion diffusion across the intermembrane bulk water (<10 ns) is evident.…”

“…[28][29][30][31][32][33][34][35][36][37][38][39][40][41] As for molecular-level computational studies, the increase in computing power in the past few years has made it possible to extend computer simulations beyond the relatively long relaxation times of tens to hundreds of nanoseconds required for equilibration of ions in lipid/water systems. Although most computational studies by far have focused on the effects of salt ions on zwitterionic (neutral) lipid bilayers, 33,[42][43][44][45][46][47][48][49][50][51][52][53] there is also an increasing number of studies on anionic [54][55][56][57][58][59] and cationic 60,61 lipid bilayers. Most simulations have addressed the effect of ions on the structural and electrostatic properties of lipid membranes.…”

Collective Dynamics in Lipid Membranes: From Pore Formation to Flip-Flops

“…However, ionic leakage through the pore is found to be sensitive to the type of cation: K ions permeate through a lipid membrane much easier than Na ions do. The origin of such a difference is most likely in the strong interactions of sodium ions with lipid headgroups lining the pore walls [43][44][45][46][47]. In contrast, potassium ions interact only weakly with the carbonyl regions of phospholipids [11,47].…”

“…This finding can readily be explained in terms of interactions of cations with lipid headgroups: sodium ions demonstrate much stronger interactions with zwitterionic phosphatidylcholine lipids than potassium ions [11,47]. More specifically, sodium ions are known to bind strongly to carbonyl oxygens of phosphatidylcholines, leading to the formation of tight complexes between neighboring lipids [11,[43][44][45][46][47], thus weakening the desorption of lipids out of membrane leaflets toward the membrane interior. Overall, the molecular mechanism of lipid flip-flop discussed here consists of two steps [34].…”