Multiscale Computational Insights into Bergenin Encapsulation by Modified γ-Cyclodextrins: Conformational and Energetic Investigations via QM/MM and Molecular Dynamics

Despite bergenin (BER) having significant therapeutic benefits, its medicinal potential is hindered by its low natural abundance and poor aqueous solubility. Through host-guest complexation with cyclodextrins (CDs), this work offers an economical molecular approach to increase the bioavailability of BER. For the three native CDs (α-, β-, and γ-CD), γ-CD showed superior encapsulation properties. Octakis(6-O-sulfo)-γ-CD and Octakis(2,3,6-tri-O-methyl)-γ-CD were found to be the most suitable hosts for BER after additional screening of γ-CD derivatives. Strong non-bonded interactions and improved conformational stability were found for both complexes in microsecond-scale (2 μs) molecular dynamics (MD) simulations. Counterpoise-corrected DFT calculations at the B3LYP/6-31+G level showed more favorable complexation energy for the Octakis-methyl-γ-CD/BER complex (-52.34 kJ/mol) than for the Octakis-sulfo-γ-CD/BER complex (-33.81 kJ/mol), a trend that was consistently reproduced using the ωB97X-D/6-31G level of theory. Steered MD simulations demonstrated the unbinding mechanism of BER from CD. Higher electronic stability for the methylated complex (8.42 eV gap) than the sulfonated complex (7.01 eV) was shown by HOMO-LUMO orbital energy analysis. This higher stability of Octakis(2,3,6-tri-O-methyl)-γ-CD/BER was supported by two hydrogen bonds and one carbon-hydrogen interaction, as determined by IGMH analysis. The IR and UV-vis spectra of BER were also calculated and systematically compared with the corresponding experimental spectra. These molecular insights demonstrate that Octakis(2,3,6-tri-O-methyl)-γ-CD serves as a superior encapsulation host for BER, enhancing its therapeutic applicability.