Molecular modeling of gelatin–plasticizer interactions: Insights from DFT and molecular dynamics

Gelatin is a versatile natural biopolymer widely applied in food, pharmaceutical, and biomedical fields. Yet, its brittleness and moisture sensitivity restrict broader use in sustainable materials. While glycerol has long been the standard plasticizer, the search for eco-friendly alternatives remains pressing. In this study, gelatin interactions with natural plasticizers were examined using Density Functional Theory (B3LYP/6-31G**) and Molecular Dynamics (GROMACS, OPLS-AA, 100[Formula: see text]ns trajectories in explicit water). Plasticizers included polyols (sorbitol, mannitol, erythritol), organic acids (citric, succinic), amino acids (glycine, arginine), and amides (urea, thiourea). Hydrogen-bonding patterns, binding free energies, and electronic properties were systematically evaluated. All plasticizers formed stable H-bond networks with gelatin. Sorbitol and arginine generated the highest number of bonds (10–12 per cluster), while citric acid provided strong cross-linking. Normalized interaction energies reached [Formula: see text][Formula: see text]kcal/mol, confirming thermodynamic stabilization. Thiourea showed unique sulfur-mediated coordination, suggesting enhanced flexibility. MD simulations confirmed complex stability (RMSD[Formula: see text][Formula: see text][Formula: see text]0.25[Formula: see text]nm, stable radii of gyration), with [Formula: see text] ranging from [Formula: see text][Formula: see text]kcal/mol (urea) to [Formula: see text][Formula: see text]kcal/mol (glycerol). Agreement with literature data supports the predictive power of the approach. For the first time, combined DFT and MD modeling were applied to gelatin–plasticizer systems, offering molecular insights to guide the design of biodegradable, tunable gelatin-based films for food, packaging, and biomedical applications.