Atomic-scale insights into the interaction mechanism of carmustine on chitosan nanocarriers: A combined DFT and molecular dynamics study.

In this study, density functional theory (DFT) calculations and molecular dynamics (MD) simulations were combined to investigate the interaction mechanism and drug-loading performance of chitosan (CS) as a carrier for carmustine (BCNU). DFT results indicate that adsorption of BCNU onto the CS surface is an exothermic process, with adsorption energies ranging from -8.69 to -26.41 kcal·mol-1. The complexes are primarily stabilized by hydrogen bonding and van der Waals (vdW) interactions. Among them, complex D exhibits the most negative adsorption energy and the greatest structural stability. FMO analyses show that the HOMO is mainly localized on CS, whereas the LUMO is localized on BCNU. The complexes exhibit a smaller Eg than isolated BCNU and show enhanced electrophilicity relative to isolated CS, which is beneficial for the chemical reactivity of the drug. QTAIM and NCI analyses confirm that medium strength hydrogen bonds and vdW forces dominate the non-covalent interactions between CS and BCNU. MD simulations reveal the assembly behavior and stability of the complexes at different drug loading ratios. Among the studied systems, the 8BCNU@8CS complex with a drug loading of 14.08 wt% exhibits the lowest mean square displacement and solvent accessible surface area, suggesting a more compact and stable encapsulation structure, which may be conducive to achieving sustained release based on simulation conditions. This work elucidates the atomic-scale interaction mechanisms between CS and BCNU and provides a theoretical basis for designing efficient, stable CS-based nanocarriers for BCNU delivery.