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

Protein functionalization is intrinsically solvent-dependent, with ionic liquids (ILs) capable of significantly perturbing protein dynamics through interactions with peptide backbones. As the correlated motion of peptide regulates intramolecular signal transmission, IL-dipeptide interactions critically influence protein structure and functional regulation, emphasizing 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 cooperative contribution from both, depending on the chemical nature of the constituent A. Notably, electrostatic nature dominates in an 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.