Amphiphilic interactions of ionic liquids with lipid biomembranes: a molecular simulation study

Abstract

Current bottlenecks in the large-scale commercial use of many ionic liquids (ILs) include their high costs, low biodegradability, and often unknown toxicities. As a proactive effort to better understand the molecular mechanisms of ionic liquid toxicities, the work herein presents a comprehensive molecular simulation study on the interactions of 1-n-alkyl-3-methylimidazolium-based ILs with a phosphatidylcholine (PC) lipid bilayer. We explore the effects of increasing alkyl chain length (n = 4, 8, and 12) in the cation and anion hydrophobicity on the interactions with the lipid bilayer. Bulk atomistic molecular dynamics (MD) simulations performed at millimolar (mM) IL concentrations show spontaneous insertion of cations into the lipid bilayer regardless of the alkyl chain length and a favorable orientational preference once a cation is inserted. Cations also exhibit the ability to "flip" inside the lipid bilayer (as is common for amphiphiles) if partially inserted with an unfavorable orientation. Moreover, structural analysis of the lipid bilayer show that cationic insertion induces roughening of the bilayer surface, which may be a precursor to bilayer disruption. To overcome the limitation in the timescale of our simulations, free energies for a single IL cation and anion insertion have been determined based on potential of mean force calculations. These results show a decrease in free energy in response to both short and long alkyl chain IL cation insertion, and likewise for a single hydrophobic anion insertion, but an increase in free energy for the insertion of a hydrophilic chloride anion. Both bulk MD simulations and free energy calculations suggest that toxicity mechanisms toward biological systems are likely caused by ILs behaving as ionic surfactants. [Yoo et al., Soft Matter, 2014].

Effect of ionic liquids on the interaction between liposomes and common wastewater pollutants investigated by capillary electrophoresis

“…The lipophilic alkyl chain of the IL penetrates into the hydrophobic region of the lipid bilayer making it rough. This can induce disruption and leakage of the lipid bilayer and eventually cell death [12][13][14][15]. However, short chained amidium and imidazolium ILs showed no significant cytotoxicity under the tested conditions.…”

“…They noticed that the alkyl chains of the tested ILs were deeply inserted into the hydrophobic region of the phospholipid bilayers and the penetration was dependent on the alkyl chain length. The penetration of the ILs increased the lateral movement of the lipids and moreover, with increasing IL concentrations the surface became rough, which could be a precursor for bilayer disruption [14].…”

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

“…Further investigations into the connection between cytotoxicity, cation chain length, and RTIL concentration have been done by Maginn and co-workers by combining several experimental techniques with computer simulations (Yoo et al 2014(Yoo et al , 2016a. Their main result was the concentration-dependence study of RTILs on biomembranes.…”

“…This article is part of a Special Issue on 'IUPAB Edinburgh Congress' edited by Damien Hall (v) Penetrate, create pores, and destroy biomembranes (Benedetto et al 2014b, Bhattacharya et al 2017, Evans 2008, Yoo et al 2014, b, Wang et al 2015a, b, 2016Drücker et al 2017; and (vi) Dissolve cellulose and other complex polysaccharides (Youngs et al 2011, Zhang et al 2017, Cheng et al 2011, Liu et al 2010.…”

Efficacy of ionic liquids on the growth and simultaneous xylanase production by Sporotrichum thermophile: membrane integrity, composition and morphological investigation

“…47 The anions moiety of the ILs on the other hand have also been reported to get inserted in the lipid bilayer. 48 The morphological effects of such phenomenon is the alteration in cell membrane permeability as well as its cellular functions. 19 In a similar study, ILs have been shown to disrupt the ion channels in the membrane thereby disturbing the homeostasis.…”