Molecular dynamics simulations of cyclodextrin–cumene hydroperoxide complexes in water

It has well been known that glutathione peroxidase (GPX) mimics based on cyclodextrins (CDs) have great selectivity to hydroperoxide substrates and the preferred hydroperoxide is the aromatic cumene hydroperoxide (CuOOH). The reduction of CuOOH often proceeds much faster than reduction of the more hydrophilic hydroperoxides. The purpose of this study is to provide theoretical evidence of this substrate specificity mechanism. In this contribution, we report our investigation on the intermolecular interaction and modeling calculations on the complexes of three cyclodextrins, viz. α-, β-, and γ-CD, with CuOOH by means of computational molecular dynamics (MD) simulations. The free energy profile along the ordering parameter, association constant, and the corresponding association free energy, as well as the most important interactions which contribute to their stability were studied in detail. The results show that stable inclusion complexes only form when both the host and guest molecules experience a significant decrease in the complexing potential. Among the three CDs, β-CD exhibits the highest propensity to associate with CuOOH. Ranking for binding CuOOH, viz. β-CD > γ-CD > α-CD.