Molecular Dynamics Simulations of Asymmetric NaCl and KCl Solutions Separated by Phosphatidylcholine Bilayers: Potential Drops and Structural Changes Induced by Strong Na+-Lipid Interactions and Finite Size Effects

Abstract

Differences of ionic concentrations across lipid bilayers are some of the primary energetic driving forces for cellular electrophysiology. While macroscopic models of asymmetric ionic solutions are well-developed, their connection to ion, water, and lipid interactions at the atomic scale are much more poorly understood. In this study, we used molecular dynamics to examine a system of two chambers of equal ionic strength, but differing amounts of NaCl and KCl, separated by a lipid bilayer. Our expectation was that the net electrostatic potential difference between the two chambers should be small or zero. Contrary to our expectation, a large potential difference (-70 mV) slowly evolved across the two water chambers over the course of our 172-ns simulation. This potential primarily originated from strong Na(+) binding to the carbonyls of the phosphatidylcholine lipids. This ion adsorption also led to significant structural and mechanical changes in the lipid bilayer. We discuss this surprising result in the context of indirect experimental evidence for Na(+) interaction with bilayers as well as potential caveats in current biomembrane simulation methodology, including force-field parameters and finite size effects.

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.…”

“…[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.…”

Intrinsic Potential of Cell Membranes: Opposite Effects of Lipid Transmembrane Asymmetry and Asymmetric Salt Ion Distribution

“…This result is in line with refs 16 and 21: The effect of KCl salt on a PC membrane is highlighted by a slight increase in the electrostatic potential across a monolayer as compared to a salt-free solution. In particular, for the force field employed for ions in ref 17, it was shown 30 that the potassium-induced increase in membrane potential is around 12 mV. Therefore, substitution of a salt-free water bath considered in ref 16 with KCl saline solution should lead to a transmembrane potential drop of 85 -12 ) 73 mV, which almost coincides with the result of Baker et al 17 In our case, KCl salt is in contact with POPE lipids, which are known to be quite insensitive to potassium ions.…”

“…In particular, for the force field employed for ions in ref 17, it was shown 30 that the potassium-induced increase in membrane potential is around 12 mV. Therefore, substitution of a salt-free water bath considered in ref 16 with KCl saline solution should lead to a transmembrane potential drop of 85 -12 ) 73 mV, which almost coincides with the result of Baker et al 17 In our case, KCl salt is in contact with POPE lipids, which are known to be quite insensitive to potassium ions. 30 Therefore, one can expect the potential difference to be around 85-90 mV, which is indeed the case.…”

Computer simulations of alkali-acetate solutions: Accuracy of the forcefields in difference concentrations

“…Non-polarizable forcefields have been used routinely and successfully to study proteins and other macromolecules, typically in NaCl or KCl solutions [27][28][29][30][31][32][33][34][35] . Interestingly, using energy decomposition analysis (EDA) we have recently found out that polarization contributes 29% of the interaction free energy between Li + and firstshell water molecules and as much as 23-25% of the same interaction for Na + .…”