title: Molecular basis of binding and stability of curcumin in diamide-linked γ-cyclodextrin dimers.
abstract: Curcumin is a naturally occurring molecule with medicinal properties that is unstable in water, whose efficacy as a drug can potentially be enhanced by encapsulation inside a host molecule. In this work, the thermodynamics and mechanism of binding of curcumin to succinamide- and urea-linked γ-cyclodextrin (γ-CD) dimers in water are investigated by molecular dynamics simulations. The simulated binding constants of curcumin to succinamide- and urea-linked γ-CD dimers at 310 K are 11.3 × 10(6) M(-1) and 1.6 × 10(6) M(-1), respectively, matching well with previous experimental results of 8.7 × 10(6) M(-1) and 2.0 × 10(6) M(-1). The simulations reveal structural information about the encapsulation of curcumin inside the diamide-linked γ-CD dimers, with distinct qualitative differences observed for the two dimers. In particular, (1) the predominant orientation of curcumin inside the urea-linked γ-CD dimer is perpendicular to that in the succinamide-linked γ-CD dimer; (2) the magnitude of the angle between the planes of the cyclodextrins is larger for the succinamide-linked γ-CD dimer; and (3) curcumin exhibits greater configurational freedom inside the urea-linked γ-CD dimer. A consequence of some of these structural differences is that the dimer interior is more accessible to water in the succinamide-linked γ-CD dimer. These observations explain the higher stability and lower binding constant observed experimentally for curcumin in the urea-linked cyclodextrin γ-CD dimer compared with the succinamide-linked γ-CD dimer. More generally, the results demonstrate how stability and binding strength can be decoupled and thus separately optimized in host-guest systems used for drug delivery.
authors.affiliation: School of Chemistry and Physics, The University of Adelaide , Adelaide, SA 5005, Australia.
authors.forename: Samuel J
authors.initials: SJ
authors.lastname: Wallace
authors.forename: Tak W
authors.initials: TW
authors.lastname: Kee
authors.forename: David M
authors.initials: DM
authors.lastname: Huang
mesh_terms: D001665:Binding Sites; D003474:Curcumin / Q000737:chemistry*; D003958:Diamide / Q000737:chemistry*; D019281:Dimerization; D008958:Models, Molecular; D015394:Molecular Structure; D047408:gamma-Cyclodextrins / Q000737:chemistry*
chemical_list: D047408:gamma-Cyclodextrins; D003958:Diamide; D003474:Curcumin; C023792:gamma-cyclodextrin