Effect of Molecular Conformation and Deformation Energy on Stability of β-Cyclodextrin Inclusion Complexes with Epi-Type Catechins in Water

This study investigated the inclusion complexation mechanisms between epi-type catechins and β-cyclodextrin (βCD) in aqueous solution through isothermal titration calorimetry (ITC), rotating-frame nuclear Overhauser effect spectroscopy (ROESY), and molecular modeling simulations (MMS). The ITC measurements revealed that gallate-type catechins, especially epicatechin gallate (ECg), interact more strongly with βCD than epicatechin (EC), as evidenced by higher association constants and favorable enthalpic contributions. ROESY analysis revealed that the aromatic rings of ECg and EC are predominantly inserted into the βCD cavity. MMS further demonstrated that ECg adopts orthogonal conformations in solution, and during complex formation, ECg and βCD undergo structural deformation and form multiple intermolecular hydrogen bonds, which contributes to stabilization. By contrast, EC maintains a planar conformation with minimal strain, resulting in weaker interactions and reduced ability to form a stable complex with βCD. Importantly, in aqueous solution, gallate-type catechins (ECg and epigallocatechin gallate) formed more stable complexes than non-gallate-type catechins (EC and epigallocatechin), highlighting the critical role of the galloyl group and the hydrophobic B-ring in stabilizing the inclusion complexes with βCD. By integrating experimental and computational approaches, we elucidated inclusion modes of catechins into the βCD cavity in solution, which cannot be captured using crystallographic data alone. These findings provide novel insights into catechins–βCD inclusion complexes, beyond crystallographic analysis, and offer important implications for understanding and optimizing their structural features and intermolecular interactions with βCD.