Molecular recognition by β-cyclodextrin derivatives: FEP vs MM/PBSA study

The complexation of p-tert-butylphenyl p-tert-butylbenzoate, N-(p-tert-butylphenyl)-p-tertbutylbenzamide and a bisadamantyl-phosphate derivative with a β-cyclodextrin derivative formed by two cyclodextrin units linked by a disulfide bridge on one of the C6 atoms have been studied by computational methods (free energy perturbation (FEP) and Molecular Mechanics/Poisson Bolzmann Surface Area (MM/PBSA)). The calculated relative free energies of the amide and ester are in good agreement with experiment only for MM/PBSA and not for FEP. Only MM/PBSA was applied to the bisadamantyl -phosphate complex and its calculated association free energy was calculated to be similar to that of the ester, which is consistent with the experimental tendencies.