Fluoride-selective binding in a new deep cavity calix[4]pyrrole: experiment and theory.

A new "super-extended cavity" tetraacetylcalix[4]pyrrole derivative was synthesized and characterized, and X-ray crystal structures of complexes bound to fluoride and acetonitrile were obtained. The binding behavior of this receptor was investigated by NMR titration, and the complex was found to exclusively bind fluoride ions in DMSO-d(6). This unusual binding behavior was investigated by Monte Carlo free energy perturbation simulations and Poisson calculations, and the ion specificity was seen to result from the favorable electrostatic interactions that the fluoride gains by sitting lower in the phenolic cavity of the receptor. The effect of water present in the DMSO on the calculated free energies of binding was also investigated. Owing to the use of a saturated ion solution, the effect of contaminating water is small in this case; however, it has the potential to be very significant at lower ion concentrations. Finally, the adaptive umbrella WHAM protocol was investigated and optimized for use in binding free energy calculations, and its efficiency was compared to that of the free energy perturbation calculations; adaptive umbrella WHAM was found to be approximately two times more efficient. In addition, structural evidence demonstrates that the protocol explores a wider conformational range than free energy perturbation and should therefore be the method of choice. This paper represents the first complete application of this methodology to "alchemical" changes.