Ionic liquids as anti-bacterial and drug delivery agent: How cation amphiphilic structure controls morphology changes in lipid bilayers and penetration mechanism

Ionic liquids based technologies are promising both as anti-bacterial and in drug delivery, being able to improve drugs solubility and capacity to bypass lipid bilayers while also taking advantage of ionic liquids physical properties like negligible vapor pressure and stability. In both applications, it is imperative to understand how the molecular structure of the ionic liquid determines the interaction with cellular membranes. In this work, molecular dynamics simulations with coarse-grained models were applied to study the penetration of eight ionic liquids based on 1,3-dialkyl-imidazolium cation with different alkyl groups size into DPPC bilayers from both dilute and concentrate aqueous solutions. Potential of mean force calculations were performed to evaluate the thermodynamics of cation penetration, and graph theory was used to characterize their non-homogeneous distributions inside the bilayers. Distinct effects were noticed over bilayer morphology: Cations with a single small or medium alkyl tail don’t induce significant changes over the bilayer structure, while cations with a 16-carbon-atom chain are water insoluble and, in concentrated solutions, are capable of partially removing lipid molecules. Incorporated cations with two medium-sized tails remain close to the water interface, reducing the interaction between lipids and decreasing the bilayer thickness, while cations with two large tails penetrate into the hydrophobic center of the bilayer and increase its thickness instead. As a consequence of the different interactions, two different mechanisms were proposed for the drug delivery action of the ionic liquids, depending on their water solubility and clustering tendency.