Mechanistic insights into Cyclodextrin-mediated modulation of curcumin-BSA interactions: Integrated spectroscopic and...

Cyclodextrins (CDs) have shown significant efficacy in enhancing the aqueous solubility and chemical stability of curcumin (CUR). However, their impact on the interaction between serum albumin and CUR remains inadequately understood, despite the potential implications for CUR's tissue distribution, metabolism, and bioavailability. In this study, the effect of hydroxypropyl-β-cyclodextrin (HPβCD) on the interaction between bovine serum albumin (BSA) and CUR was investigated using multispectral techniques, molecular docking, and molecular dynamics (MD) simulations. Multispectral analysis revealed that HPβCD exhibited negligible binding affinity for BSA but markedly attenuated the direct interaction between BSA and CUR by competitively complexing with CUR. At 298 K, the binding constant of the BSA-CUR complex decreased from 6.22 × 10⁶ to 1.60 × 10⁶ L/mol after the addition of HPβCD. Concurrently, HPβCD mitigated CUR-induced conformational and microenvironmental alterations in BSA, reducing the α-helical content from 63.5% to 55.9%. Molecular docking indicated binding affinities in the following order: BSA-CUR > HPβCD-CUR > BSA-HPβCD, which is corroborated by MD-based thermodynamic binding free energies calculated using the Molecular Mechanics Poisson-Boltzmann Surface Area method. Moreover, MD simulations revealed that CUR existed in two distinct states, either complexed with HPβCD or bound to BSA after dissociation from the carrier, while no stable interaction formed between BSA and HPβCD. These findings elucidate the competitive binding mechanisms in the ternary BSA-CUR-HPβCD system, offering a molecular basis for designing CUR-CD formulations with tunable protein-binding properties.