Hydration Pattern of Ionic Liquids in the Stabilization of Insulin Dimer: A Computational Perspective

Abstract Choline [Cho]‐based ionic liquids (ILs) are biodegradable and soluble and have shown strong application in the protein stabilization and drug delivery. In this work, the stability of the insulin dimer is investigated in the presence of [Cho]‐based ILs containing three distinct anions (i.e., acetate [OAc], taurate [Tau], and geranate [Ger]). Molecular dynamics (MD) simulations and density functional theory (DFT) calculations explore insulin's stability and structure in the presence of ILs. MD analyses reveal that the insulin dimer is stabilized by non‐covalent interactions, with hydrogen bonds and anions in ILs playing key roles. Among them, [Cho][OAc] ILs show significantly better stabilization than other anions.This is due to the hydration patterns of acetate anion, which can be compared to Hofmeister series and chemical agent effects (i.e., kosmotrope and chaotrope). Further, non‐covalent interactions index and electron density analyses from the atoms‐in‐molecules theory approach are carried out to quantify the strength of non‐covalent interaction in ILs with water clusters (Wn, n = 0–6). Analyses show the significance of water molecules in the stabilization of insulin dimer in the presence of [Cho]‐based ILs. The study elucidates the role of ILs formulation concerning insulin dimers to improve the transdermal and oral drug delivery systems.