Explicit Solvation Effects on the Redox Thermodynamics of Fe(III)/Fe(II)-Quercetin Complexes: A DFT/MD Study

Explicit solvent effect on the redox thermodynamics of Fe(III)/Fe(II)-quercetin complexes in aqueous solution was investigated using a multiscale approach combining density functional theory (DFT) and molecular dynamics (MD) simulations. Complexation of quercetin with Fe was initially evaluated at the ωB97XD/def2-TZVP//def2-SVP level of theory using the implicit solvation model (SMD). The most stable 1:1 ML complex was identified as a bidentate Fe(III) complex at the O6O7 position, while the lowest-energy 1:2 ML2 complex corresponded to model C2, with approximately orthogonal quercetin ligands. Local solvent interactions were studied by adding up to 15 explicit water molecules around the quercetin-Fe solute, resulting in reduced reaction enthalpy and free energy of the clusters compared to the purely implicit model. Furthermore, the enthalpy and free energy of the reduction of Fe(III) in the presence of an ascorbate anion generally increase with the number of explicit waters. The differential solvent contribution was also examined using free energy perturbation (FEP) calculations within MD simulations. Overall, our findings underscore the role of the explicit solvation model in calculating the redox thermodynamics properties of iron couples in aqueous environments, highlight quercetin's potential as an anti-Fenton agent, and offer valuable insights for antioxidant research, biological, and environmental applications.