Molecular and quantum mechanical insights of conformational dynamics of Maltosyl-β-Cyclodextrin/Formononetin supramolecular complexes

Formononetin (FMN), a highly promising bioactive molecule, faces solubility challenges that hinder its biological activity. To enhance its solubility, β-cyclodextrin (β-CD) and its derivative, 6-O-α-Maltosyl-β-CD (M-β-CD), were employed. In this study, four inclusion complexes were studied, namely β-CD:FMN and three conformations of M-β-CD:FMN (M-β-CD1:FMN, M-β-CD2:FMN, and M-β-CD3:FMN). The molecular-level examination explored the thermodynamics and driving forces underlying the inclusion reaction, utilizing a combined approach of molecular mechanics and quantum mechanics (QM). Microsecond timescale classical and biased molecular dynamics simulations were conducted to analyze FMN's dynamics within the CD cavity. Accurate energetic descriptions of inclusion complexes were obtained via two-layered Our own N-layered Integrated molecular Orbital and Molecular mechanics (ONIOM) method employing wB97X-D/6–311 + G(d,p):PM7 model chemistry. The umbrella sampling and QM analyses unveiled that M-β-CD, particularly in the M-β-CD1:FMN inclusion complex, tightly encapsulated FMN. This was attributed to additional non-covalent interactions (NCIs) facilitated by the maltosyl chain, resulting in the most favorable complexation energy (-239.25 kJ/mol) and Gibbs free energy (-221.55 kJ/mol). The study elucidated critical atoms involved in NCIs, with NCI-RDG analysis providing insights into the nature of these interactions. Conformational dynamics of the three M-β-CD:FMN complexes revealed the optimal FMN orientation within the M-β-CD cavity. This computational approach sets a standard for improving the solubility of various biologically significant molecules.