Interaction of Choline-Based Ionic Liquids with Model Lipid Membranes: Force-Field Parametrization and Membrane...

In recent years, ionic liquid (IL)-based formulations have gained attention for their potential use in drug delivery and antibacterial and antiseptic applications. Molecular dynamics simulations can provide insights into complex interaction mechanisms, serving as valuable tools to guide experimental efforts to design novel formulations. However, to study interactions that involve micellar aggregates and membrane partitioning dynamics, simulations should be able to access time scales of several microseconds, requiring reliably parametrized coarse-grained molecular models. In this study, we investigate the interaction of choline-geranic acid (CAGE)-based ILs with a model phospholipid membrane. In order to develop a coarse-grained CAGE model, we carried out atomistic simulations with the GROMOS54a7, CHARMM36m, OPLS, and OPLS-R force fields. The OPLS-R force field was found to accurately predict experimental structural and dynamic properties of CAGE molecules and was therefore used to parametrize the coarse-grained models within the Martini 2 (M2) and Martini 3 (M3) frameworks. The M3 model was in better agreement with both experimental observations and atomistic simulations and captured the reported micellar phase transition composition with increasing water content. In contrast, the M2 model was found to overestimate the density, with a greater tendency to form a lamellar phase. Using the newly parametrized M3 force field, free energy computations with a dipalmitoylphosphatidylcholine (DPPC) lipid bilayer revealed a favorable free energy of partitioning for geranic acid compared to geranate ions, while choline partitioning was unfavorable. Geranate ion partitioning increased with a higher concentration of geranic acid in the CAGE solution. Micellar aggregates of geranic acid either released molecules in the extracellular space for subsequent membrane uptake or underwent direct fusion with the membrane. Both the area compressibility and order parameters decreased with increasing geranic acid content, which also resulted in an increase in the lipid area. The coarse-grained model developed in this study allows us to study membrane partitioning, micellar breakup, and membrane fusion events which occur on microsecond times scales. These models can potentially be utilized to investigate the influence of CAGE-based chemistry on membrane partitioning, thereby aiding in the development of novel IL-based therapeutic formulations.