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 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 -350 kcal/mol, confirming thermodynamic stabilization. Thiourea showed unique sulfur-mediated coordination, suggesting enhanced flexibility. MD simulations confirmed complex stability (RMSD < 0. 25 nm, stable radii of gyration), with ΔGbind ranging from -25. 6 kcal/mol (urea) to -67. 3 kcal/mol (glycerol). Agreement with literature data supports the predictive power of the approach. For the first time, combined DFT and MD modeling is applied to gelatin-plasticizer systems, offering molecular insights to guide the design of biodegradable, tunable gelatin-based films for food, packaging, and biomedical applications. 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 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 -350 kcal/mol, confirming thermodynamic stabilization. Thiourea showed unique sulfur-mediated coordination, suggesting enhanced flexibility. MD simulations confirmed complex stability (RMSD < 0. 25 nm, stable radii of gyration), with ΔGbind ranging from -25. 6 kcal/mol (urea) to -67. 3 kcal/mol (glycerol). Agreement with literature data supports the predictive power of the approach. For the first time, combined DFT and MD modeling is applied to gelatin-plasticizer systems, offering molecular insights to guide the design of biodegradable, tunable gelatin-based films for food, packaging, and biomedical applications. 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 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 -350 kcal/mol, confirming thermodynamic stabilization. Thiourea showed unique sulfur-mediated coordination, suggesting enhanced flexibility. MD simulations confirmed complex stability (RMSD < 0. 25 nm, stable radii of gyration), with ΔGbind ranging from -25. 6 kcal/mol (urea) to -67. 3 kcal/mol (glycerol). Agreement with literature data supports the predictive power of the approach. For the first time, combined DFT and MD modeling is applied to gelatin-plasticizer systems, offering molecular insights to guide the design of biodegradable, tunable gelatin-based films for food, packaging, and biomedical applications. 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 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 -350 kcal/mol, confirming thermodynamic stabilization. Thiourea showed unique sulfur-mediated coordination, suggesting enhanced flexibility. MD simulations confirmed complex stability (RMSD < 0. 25 nm, stable radii of gyration), with ΔGbind ranging from -25. 6 kcal/mol (urea) to -67. 3 kcal/mol (glycerol). Agreement with literature data supports the predictive power of the approach. For the first time, combined DFT and MD modeling is applied to gelatin-plasticizer systems, offering molecular insights to guide the design of biodegradable, tunable gelatin-based films for food, packaging, and biomedical applications.