Effect of NaCl and KCl on Phosphatidylcholine and Phosphatidylethanolamine Lipid Membranes:  Insight from Atomic-Scale Simulations for Understanding Salt-Induced Effects in the Plasma Membrane

Abstract

To gain a better understanding of how monovalent salt under physiological conditions affects plasma membranes, we have performed 200 ns atomic-scale molecular dynamics simulations of phosphatidylcholine (PC) and phosphatidylethanolamine (PE) lipid bilayers. These two systems provide representative models for the outer and inner leaflets of the plasma membrane, respectively. The implications of cation-lipid interactions in these lipid systems have been considered in two different aqueous salt solutions, namely NaCl and KCl, and the sensitivity of the results on the details of interactions used for ions is determined by repeating the simulations with two distinctly different force fields. We demonstrate that the main effect of monovalent salt on a phospholipid membrane is determined by cations binding to the carbonyl region of a membrane, while chloride anions mostly stay in the water phase. It turns out that the strength and character of the cation-lipid interactions are quite different for different types of lipids and cations. PC membranes and Na + ions demonstrate strongest interactions, leading to notable membrane compression. This finding was confirmed by both force fields (Gromacs and Charmm) employed for the ions. The binding of potassium ions to PC membranes (and the overall effect of KCl), in turn, was found to be much weaker mainly due to the larger size of a K + ion compared to Na + . Furthermore, the effect of KCl on PC membranes was found to be force-field sensitive: The binding of a potassium ion was not observed at all in simulations performed with the Gromacs forcefield, which seems to exaggerate the size of a K + ion. As far as PE lipid bilayers are concerned, they are found to be influenced by monovalent salt to a significantly lesser extent compared to PC bilayers, which is a direct consequence of the ability of PE lipids to form both intra-and intermolecular hydrogen bonds and hence to adopt a more densely packed bilayer structure. Whereas for NaCl we observed weak binding of Na + cations to the PE lipid-water interface, in the case of KCl we witnessed almost complete lack of cation binding. Overall, our findings indicate that monovalent salt ions affect lipids in the inner and outer leaflets of plasma cell membranes in substantially different ways.

Influence of the sterol aliphatic side chain on membrane properties: a molecular dynamics study

“…As we 70 and others 65,67,76,77 have recently demonstrated, small cations such as Na + bind to the ester/carbonyl atoms of phospholipids, inducing a slight enhancement of the lipid order (whereas common counter ions such as Cl À remain firmly in the aqueous phase and do not affect the lipids). Although we have not included ions in these simulations, we expect that the addition of a salt such as NaCl would lead to a systematic ordering effect, identical for all sterols along the series, and therefore all comparative conclusions of this study would be unchanged.…”

Ion Dynamics in Cationic Lipid Bilayer Systems in Saline Solutions

“…In particular, it has been demonstrated that cations (e.g., Na + ions) are able to penetrate rather deep in the lipid headgroup region. This effect has been observed in zwitterionic, 33,42,46,[50][51][52][53] anionic, 55,56,58 and slightly cationic 61 lipid bilayers. The findings agree with experimental data.…”

“…43,45,57 In contrast, using the "Berger lipids", i.e., variants of united-atom force-fields based on refs 70, 96, and 97, tight binding of Na + ions to the lipid carbonyl oxygens is found. 33,42,46,[50][51][52][53]55,56,58,61 Due to the different nature of these two force-fields, simulations using CHARMM27 lipids need to be performed with the area of the bilayer fixed, whereas Berger lipids allow simulations in the NpT ensemble, such that the bilayer can adjust its area to agree with the thermodynamic parameters. Furthermore, the carbonyl region of lipid molecules is more polar in the case of the Berger force-field, so that it attracts cations considerably stronger compared to its CHARMM counterpart.…”

“…[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.…”

Behaviour of NBD-head group labelled phosphatidylethanolamines in POPC bilayers: a molecular dynamics study

“…This situation is reminiscent of that found for POPC bilayers in the presence of NaCl, where the distributions of the cations (near the carbonyl/ glycerol region) and anions (displaced into the water phase) set up a capacitor that induces a considerable electric field in the head group region and an overall increase in the water/bilayer electrostatic potential difference. 60,62 Here, instead of residing View Article Online in the chloride atoms, the anionic charge is located in the lipid head groups, but it is still distributed more externally than the cationic charge, and the overall effect is similar.…”