Quantifying Ionic Liquid Affinity and Its Effect on Phospholipid Membrane Structure and Dynamics

Understanding the interactions between ionic liquids (ILs) and biomembranes is pivotal for uncovering the origins of IL-induced biological activities and their potential applications in pharmaceuticals. In this study, we investigate the influence of imidazolium-based ILs on the viscoelasticity, dynamics, and phase behavior of two model membrane systems: (i) lipid monolayers and (ii) unilamellar vesicles, both composed of dipalmitoylphosphatidylcholine (DPPC). Two different ILs with varying alkyl chain lengths, namely, 1-decyl-3-methylimidazolium bromide (DMIM[Br]) and 1-hexyl-3-methylimidazolium bromide (HMIM[Br]) are used to investigate the role of alkyl chain lengths. Our findings demonstrate that both ILs induce significant disorder in lipid membranes by altering the area per lipid molecule, thereby modulating their viscoelastic properties. ILs with a longer alkyl chain show stronger interactions with membranes, causing a more pronounced disorder. Fourier transform infrared spectroscopy indicates that IL incorporation shifts the membrane's main phase transition to lower temperatures and introduces gauche defects, signifying increased structural disorder. This effect is amplified by longer alkyl chains and higher IL concentrations. Quasielastic neutron scattering studies highlight that ILs markedly enhance the lateral diffusion of lipids within the membrane leaflet, with the extent of enhancement determined by the membrane's physical state, IL concentration, and alkyl chain length. The most pronounced acceleration in lateral diffusion occurs in the ordered membrane phase with higher concentrations of the longer-chain IL. Molecular dynamics simulations corroborate these experimental findings, showing that longer-chain ILs extensively disrupt lipid organization, introduce more gauche defects, increase the area per lipid, and consequently enhance lateral diffusion. This increase in the lipid fluidity and permeability provides a mechanistic basis for the observed higher toxicity associated with longer-chain ILs. These results offer critical insights into the molecular-level interactions of ILs with lipid membranes, advancing our understanding of their toxicological and pharmaceutical implications.