What is the effective dielectric constant in a β-cyclodextrin cavity? Insights from Molecular Dynamics simulations and QM/MM calculations

We report a theoretical study on polarization effects induced by the environment on a solute placed inside a β-cyclodextrin macrocycle in aqueous solution. Calculations are carried out for a simple guest molecule p-nitrochlorobenzene using a combined Molecular Dynamics and QM/MM approach. The results have allowed us to derive an effective dielectric constant for the CD-water environment in the range 3–8 that agrees well with several experimental estimations reported in the literature. The investigation emphasizes the fact that the polarization effect is practically the same for the two possible relative orientations of the host–guest complex. For substrates able to form strong specific interactions with either the CD or the water solvent, the medium effects could be different for different orientations, however. In addition, in those cases, specific medium effect would add to the purely dielectric one. This last fact can explain why experimental studies have led to a very large range of values for the effective dielectric constant of β-CDs cavities.