Highly robust quantum mechanics and umbrella sampling studies on inclusion complexes of curcumin and β-cyclodextrin.

The poor aqueous solubility of curcumin (CUR) obstructs its wide utilization in nutraceuticals, cosmetics, and pharmaceutical companies. This study is dedicated to investigate the stability of CUR inside the hydrophobic pocket of β-cyclodextrin (β-CD), hydroxypropyl-β-CD (HP-β-CD), and 2,6-Di-O-methyl-β-CD (DM-β-CD). Initially, molecular mechanics (MM) calculations and subsequently quantum mechanical (QM) calculations were performed on inclusion complexes to strengthen the MM results. We performed microsecond timescale MD simulations to observe the structural dynamics of CUR inside the cavity of CDs. We elucidated the most stable binding orientations of CUR inside the cavity of CDs based on binding free energy obtained from the Molecular Mechanics Poisson-Boltzmann Surface Area (MM-PBSA) and umbrella sampling simulations. Furthermore, the two-layered ONIOM (B3LYP/6-311+G(2d,p):PM7) method with CPCM implicit water model was used to derive the complete energetics and thermodynamics of inclusion complexes at 1:1 stoichiometry. Each inclusion reaction was exothermic and spontaneous. The chemical reactivity and kinetic stability of inclusion complexes were described by HOMO-LUMO molecular orbital energies. In conclusion, our studies revealed that HP-β-CD had the highest binding affinity for CUR with the most negative complexation energy (-6520.69 kJ/mol) and Gibb's free energy change (-6448.20 kJ/mol). The atomic-level investigation of noncovalent interactions between CUR and the hydroxypropyl groups in HP-β-CD/CUR complex may be helpful to drive new derivatives of HP-β-CD with better host capacity. The computational strategy adopted here might serve as a benchmark for increasing the solubility of numerous clinically significant molecules.