Theoretical Insights into Energetics and Structural Modulation of Dipeptides through Ionic Liquid [EMIM][TFSI] Interactions.

Protein functionalization is intrinsically solvent-dependent, with Ionic Liquids (ILs) capable of significantly perturbing protein dynamics through interactions with peptide backbones. As correlated motion of peptide regulates intramolecular signal transmission, IL–dipeptide interactions critically influence protein structure and functional regulation, emphazising the importance of their molecular-level investigation. In this study, we considered a set of dipeptides (AA) classified as neutral and ionic (mono and di) AA to explore their interaction phenomena with IL: [EMIM][TFSI]. In doing so, interactions between IL and individual amino acids (A) were also examined to establish residue-level insights. Our results reveal that each AA exhibits a distinct interaction profile with the IL, where the dominant interaction domain involves either the EMIM/TFSI or co operative contribution from both, depending on the chemical nature of the constituent A. Notably, electrostatic nature dominates in IL-ionic AA complex whereas dispersion energy emerges as the primary stabilizing factor in IL-AA complexes involving aromatic A. Overall, molecular basis of AA–IL interaction profiles establishes a robust understanding of peptide-mediated solvent dynamics and activity regulation of protein in IL.