Calix[4]arenes bridged by crown5 and crown6 moieties represent a promising class of ionophores for big alkali cations. We present a theoretical demonstration of the possible modulation of the host-guest complementarity and recognition via the conformation of the host, and the solvent. Molecular dynamics and free energy calculations are reported for the 1,3-dimethoxy-p-tert-butyl and the p-a-derivatives in the cone, 1,3-alternate, and partial cone conformations, simulated in the gas phase and in water. In the gas phase, a decrease in binding affinity is calculated for the three forms of the complexes, from Na+ to Cs+. Intrinsically, the largest ions prefer clearly the 1,3-alternate conformers, while Na+ prefers slightly the cone conformers. In aqueous solution, the change in free energy for mutating the Na+ calix[4]-crown6 complex to the Cs+ complex depends markedly on the conformation of the calixarene, and is about 12 kcal/mol weaker for the 1,3-alternate than for the cone form. Taking into account the difference in desolvation energy of the cations (30.4 kcal/mole) leads therefore to conformation dependent Na+/Cs+ binding selectivity. We predict that Na+ is bound selectively in the cone form, while Cs' is preferred in the 1,3-alternate form, while the partial cone displays no clear Na+/Cs+ preference. The selectivity is related to the differences in precise cation location and shielding from the solvent, as a function of the conformation of the host. We conclude that the selective binding of Cs+ by the 1,3 alternate calix[4]-crown6 is related to solvation effects, rather than to enhanced M(+)/pi interactions with the aromatic fragments. In non-aqueous solutions such as methanol or acetonitrile, the alternate form of calix[4]-crown6 is predicted to also bind Cs+ better than Na+. In dry chloroform, the situation is expected to be close to the gas phase, i.e. Na+ preferred by all three conformers. For the smaller calix[4]-crown5 host similar conformation dependent binding selectivity are predicted. Finally, we report the first MD simulations on Na+ and Cs+ complexes of the p-tert-butylcalixC6 ionophore at the water I chloroform interface with an explicit representation of the solvents. The complexes are found to behave as surfactants. After 100 ps they remain close to the interface but sit almost exclusively in the organic phase.
