Investigation of Ion Channel Activities of Gramicidin A in the Presence of Ionic Liquids Using Model Cell Membranes

Abstract

Ionic liquids (ILs) are considered to be green solvents because of their non-volatility. Although ILs are relatively safe in the atmospheric environment, they may be toxic in other environments. Our previous research showed that the cytotoxicity of ILs to biological organisms is attributable to interference with cell membranes by IL insertion. However, the effects of ILs on ion channels, which play important roles in cell homeostasis, have not been comprehensively studied to date. In this work, we studied the interactions between ILs and lipid bilayer membranes with gramicidin A ion channels. We used two methods, namely electrical and fluorescence measurements of ions that permeate the membrane. The lifetimes of channels were increased by all the ILs tested in this work via stabilizing the compressed structure of the lipid bilayer and the rate of ion flux through gA channels was decreased by changing the membrane surface charge. The former effect, which increased the rate of ion flux, was dominant at high salt concentrations, whereas the latter, which decreased the rate of ion flux, was dominant at low salt concentrations. The effects of ILs increased with increasing concentration and alkyl chain length. The experimental results were further studied using molecular dynamics simulations.

Room-temperature ionic liquids meet bio-membranes: the state-of-the-art

“…In Lim et al, for example, the mutual interaction between RTIL cations once absorbed into the membrane has been studied, and the measured increment of permeability due to the absorption of RTILs has been related to their antibacterial activity. Investigations focused on specific cases and more complex systems, moreover, have enriched even more the broad and diverse panorama presented above (Patel et al 2016;Modi et al 2011;Jeong et al 2012;Ryu et al 2015;Lee et al 2015). An interesting example is the study of Jeon, Lee and co-workers on the effect of RTILs on the ion channel function of Gramicidin A embedded in a phospholipid bilayer (Jeong et al 2012;Ryu et al 2015;Lee et al 2015).…”

“…Investigations focused on specific cases and more complex systems, moreover, have enriched even more the broad and diverse panorama presented above (Patel et al 2016;Modi et al 2011;Jeong et al 2012;Ryu et al 2015;Lee et al 2015). An interesting example is the study of Jeon, Lee and co-workers on the effect of RTILs on the ion channel function of Gramicidin A embedded in a phospholipid bilayer (Jeong et al 2012;Ryu et al 2015;Lee et al 2015). Their results show for the first time how the changes of the physical properties of the biomembrane (e.g., thickness) induced by the absorption of RTIL cations can influence the activities of membrane proteins (Fig.…”

Effects of imidazolium-based ionic liquids on the stability and dynamics of gramicidin A and lipid bilayers at different salt concentrations

“…The final system consists of a gA dimer, 122 DOPC or DMIM (61 DOPC or DMIM per leaflet), ∼5000 water molecules, and enough Na + and Cl − ions to neutralize the system, leading to the salt concentrations of 0.15 M and 1 M NaCl. Note that electrical and fluorescence experiments were performed at 1 M NaCl and 0.14 M NaNO 3 , respectively [26]. In this work, salts of 1 M and 0.15 M NaCl were used to investigate the concentration effect of the same type of salt, although it cannot be ruled out that NaCl and NaNO 3 might yield different electrostatic properties of the simulated systems.…”

“…Real space cutoffs of 14 Å and 11 Å were respectively applied for Lennard-Jones (LJ) and electrostatic forces with the inclusion of particle mesh Ewald summation [44] for long-range electrostatics. A temperature of 298 K, which is similar to the experimental condition [26], and a pressure of 1 bar were maintained by applying the velocity-rescale thermostat [45] and Berendsen barostat [46] in the NP xy P z T ensemble (semi-isotropic pressure coupling). The LINCS algorithm was used to constrain the bond lengths.…”

“…This was also confirmed by observing the reduced transition temperature of membranes for ILs with longer tails at high concentrations. Ryu et al recently performed electrophysiological and fluorescent experiments with the peptide gramicidin A (gA) in the bilayer consisting of ILs and phospholipids [26]. Since the gA peptides, which laterally diffuse along each leaflet of the bilayer, can dimerize to form the ion chan- nel, the stability and dynamics of the bilayer can be predicted by analyzing the extent of the gA-induced pore formation.…”