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 gamma-cyclodextrin (gamma-CD) dimers in water are investigated by molecular dynamics simulations. The simulated binding constants of curcumin to succinamide- and urea-linked gamma-CD dimers at 310 K are 11.3 x 10(6) M-1 and 1.6 X 10(6) M-1, respectively, matching well with previous experimental results of 8.7 X 10(6) M-1 and 2.0 x 10(6) M-1. The simulations reveal structural information about the encapsulation of curcumin inside the diamide-linked gamma-CD dimers, with distinct qualitative differences observed for the two dimers. In particular, (1) the predominant orientation of curcumin inside the urea-linked gamma-CD dimer is perpendicular to that in the succinamide-linked gamma-CD dimer; (2) the magnitude of the angle between the planes of the cydodextrins is larger for the succinamide-linked gamma-CD dimer; and (3) curcumin exhibits greater configurational freedom inside the urea-linked gamma-CD dimer. A consequence of some of these structural differences is that the dimer interior is more accessible to water in the succinamide-linked gamma-CD dimer. These observations explain the higher stability and lower binding constant observed experimentally for curcumin in the urea-linked cyclodextrin gamma-CD dimer compared with the succinamide-linked gamma-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.