Impact of an Ionic Liquid on Amino Acid Side Chains: A Perspective from Molecular Simulation Studies

Ionic liquids (ILs) are known to modify the structural stability of proteins. The modification of the protein conformation is associated with the accumulation of ILs around the amino acid (AA) side chains and the nature of interactions between them. To understand the microscopic picture of the structural arrangements of ILs around the AA side chains, room temperature molecular dynamics (MD) simulations have been carried out in this work with a series of hydrophobic, polar and charged AAs in aqueous solutions containing the IL 1-butyl-3-methylimidazolium tetrafluoroborate ([BMIM][BF₄]) at 2 M concentration. The calculations revealed distinctly nonuniform distribution of the IL components around different AAs. In particular, it is demonstrated that the BMIM⁺ cations preferentially interact with the aromatic AAs through favorable stacking interactions between the cation imidazolium head groups and the aromatic AA side chains. This results in preferential parallel alignments and enhanced population of the cations around the aromatic AAs. The potential of mean force (PMF) calculations revealed that such favorable stacking interactions provide greater stability to the contact pairs (CPs) formed between the aromatic AAs and the IL cations as compared to the other AAs. It is further quantified that for most of the AAs (except the cationic ones), a favorable enthalpy contribution more than compensates for the entropy cost to form stable CPs with the IL cations. These findings are likely to provide valuable fundamental information toward understanding the effects of ILs on protein conformational stability.