Effect of mixtures of ionic liquids and water on the structure and stability of the insulin dimer: a combined DFT and MD simulation study

Biocompatible cholinium-based ionic liquids (ILs) are used extensively in the pharmaceutical and biomedical industries. To enhance structural stability and solubility of drugs, as well as their controlled delivery, IL-based active pharmaceutical ingredients (API) are used widely. In this study, we selected two different sets of biodegradable ILs which also have a direct influence on the structure and stability of insulin. Moreover, we used DFT-based electronic structure calculations with molecular dynamics (MD) simulations to study the effect of a mixture of two different anions in the IL medium and the role of water molecules on the stability of insulin. Microhydration and molecular-level DFT calculations suggest that ILs based on choline geranate [Cho][Ger] and choline taurine [Cho][Tau] differ in their hydration patterns, and thus the stability of the clusters varies significantly. This finding is important for exploring the role of water molecules within these mixtures (i.e., on the interactions between [Ger] and [Tau]). From our calculations it is found that the [Cho][Ger] IL stabilizes the insulin dimer structure strongly through water-mediated H-bonding interactions, whereas the [Cho][Ger][Tau] ternary complex destabilizes insulin. This indicates that IL mixtures over a wide range of concentrations and water molecules at the interface may influence the structural stability and enable suitable combinations of oral formulations to be predicted for drug-delivery applications. From the MD simulations, we conclude that [Cho][Ger] stabilizes the insulin dimer. Our combined DFT and MD simulations will provide valuable information for experimentalists to design and develop novel oral insulin formulations.