Modulation of Thermodynamic Profiles: Regulation of Imidazole Affinity by Porphyrin Distortion in Aqueous Solution

Investigating ligand binding to distorted iron porphyrins in aqueous solution provides insights into the structure-function relationships in hemoproteins. In this study, we examined the complexation of four imidazole ligands with two water-soluble, highly substituted iron-(III) porphyrins, dodecaphenylporphyrin (WS-DPPFe) and decaphenylporphyrin (WS-DecPPFe), using spectroscopic and thermodynamic analyses. The more strongly saddle-distorted WS-DPPFe exhibited a more negative Gibbs free energy (ΔG°) than WS-DecPPFe, indicating that increased ring distortion is a key driving force that enhances ligand affinity, even in aqueous solution. Furthermore, in contrast to CHCl₃, the affinity in aqueous solution is driven predominantly by hydrophobic and electronic effects. Thermodynamic analysis confirmed that complexation is primarily enthalpy-driven; however, the relative contributions of enthalpy (ΔH°) and entropy (ΔS°) are tightly regulated by the interplay between ring distortion and ligand sterics. Notably, the WS-DecPPFe/2-methylimidazole system deviated from the general enthalpy-entropy compensation trend. Collectively, these results suggest that molecular recognition in aqueous solution can be optimized by modulating the relative thermodynamic contributions from electronic stabilization, desolvation, molecular mobility, and steric compatibility. This study provides a physicochemical foundation for regulating hemoprotein functions through geometric modulation and offers a new perspective for the rational design of functional molecules operating in aqueous environments.