Unveiling the Intricate Supramolecular Chemistry of γ‑Cyclodextrin-Epigallocatechin Gallate Inclusion Complexes

Green tea’s main polyphenol, epigallocatechin-gallate (EgCg), garners attention for diverse health-promoting properties. Due to the limited bioavailability of EgCg, drug formulation methodologies are imperative. Herein, cyclodextrins (CDs) were employed as hosts to create the host–guest complexes. The establishment of these complexes is contingent upon the dimensions of the host cavity and the orchestration of noncovalent interactions between the constituents. Among the natural CDs, namely, α-, β-, and γ-CD, γ-CD was determined to be the optimal host for EgCg based on cavity size. To improve the stability of inclusion complexes (ICs), various derivatized forms of γ-cyclodextrin were investigated. Among these, hydroxypropyl-γ-CD (HP-γ-CD) demonstrated the highest affinity for EgCg. HP-γ-CD is synthesized by substituting hydrogen atoms in the hydroxyl groups of γ-CD with hydroxypropyl groups at five positions. Molecular dynamics simulations on the microsecond time scale were performed to analyze the internal motion of EgCg and the rotational tumbling of the complexes. The binding affinity of the ICs was quantified by using umbrella sampling techniques. The EgCg/HP-γ-CD IC displayed the most favorable binding free energy (−38.21 kJ/mol), followed by that of the EgCg/γ-CD-1 complex (−23.17 kJ/mol). DFT calculations supported these findings, with HP-γ-CD showing the most optimal complexation energy (−358.05 kJ/mol). Additionally, this study underscores the crucial role of hydroxypropyl groups in HP-γ-CD at the atomic level, contributing to its enhanced stability, which is essential for synthesizing superior cavitands for bioactive molecules.