Mechanistic Insight on BioIL-Induced Structural Alterations in DMPC Lipid Bilayer

The emerging application risks of traditional ionic liquids (ILs) toward the ecosystem have changed the perception regarding their greenness. This resulted in the exploration of their more biocompatible alternatives known as biocompatible ILs (BioILs). Here, we have investigated the impact of two such biocompatible cholinium amino acid-based ILs on the structural behavior of model homogeneous DMPC (1,2-dimyristoyl-sn-glycero-3-phosphocholine) lipid bilayer using all-atom molecular dynamics simulation technique. Two classic cholinium-amino acid-based ILs, cholinium glycinate ([Ch][Gly]) and cholinium phenylalaninate ([Ch][Phe]), which differ only by the side chain lengths and hydrophobicity of the anions, have been utilized in the present work. Simultaneous analysis of the bilayer structural properties reveals that the existence of [Ch][Gly] BioIL above a particular concentration induces phase transition from fluid phase to gel phase in the DMPC lipid bilayer. Such a freezing of lipid bilayer upon the exposure to concentrated aqueous solution of [Ch][Gly] BioIL indicates the harmfulness of this BioIL toward the cell membranes majorly containing DMPC lipids, as the cell freezing can negatively affect its stability and functionality. Despite having a more hydrophobic amino acid side chain of [Phe]- anion in [Ch][Phe], in the case of bilayer-[Ch][Phe] systems we observe the minimal impact of [Ch][Phe] BioIL on the DMPC bilayer properties up to 10 mol % concentration. In the presence of these BioIL, we observe the thickening of the bilayer and accumulation of the cations and anions of the BioILs at the interface of DMPC lipid heads and tails. The transfer free-energy profile of a [Phe]- anion from aqueous phase to membrane center also indicates the anion partitioning at lipid head-tail interface and its inability to penetrate in the lipid membrane tail region. In contrast, the free-energy profile for a [Gly]- anion offers a very high energy barrier to the insertion of [Gly]- into the membrane interior, leading to accumulation of [Gly]- anions at the lipid head-water region.