MOLECULAR-DYNAMICS AND FREE-ENERGY CALCULATIONS ON THE PECULIAR BIMODAL ALKALI ION SELECTIVITY OF AN 8-SUBUNIT CAVITAND

Molecular dynamics (MD) and free energy calculations were used to examine the cation selectivity of the cavitand 1. This cavitand and two close analogs are the only macrocyclic ionophores known to date that exhibit dual ion selectivity. Experimentally,1 the strongest binding affinity among the alkali cation series Li+-Cs+ is shown toward Cs+, which is of approximately complementary size to the cavity. However, there is also a second, weaker preference for binding Na+ over Li+ or K+. Free energy calculations were carried out on a fully solvated host-guest system for all the alkali cations, starting from a conformation identical to the highly symmetrical structure found for the 1-Cs+ complex. The calculated binding affinities reproduced the bimodal alkali ion selectivity exhibited by 1, giving semiquantitative agreement with the experimental results. Analysis of these studies and further MD studies suggest that for Li+-Rb+, two water molecules accompany the ion in the cavity of the host molecule. However, only in the case of Na+ is there an optimal arrangement of both the ion and the two waters in the cavity, thus stabilizing it compared to K+ and Li+.