We present molecular dynamics studies of the complexation of a macrobicyclic calixspherand host with guest metal cations (Na+, K+, and Rb+). By using a thermodynamic free energy perturbation method, the relative free energies of calixspherand complexation with alkali metal cations were determined. We tested two sets of van der Waals parameters, two methods of describing 1-4 nonbonded interactions and two extreme models of solvation for the calixspherand-alkali ion complex. Independent of model, the calculations correctly reproduced the tighter binding to the calixspherand of K+ compared to the smaller Na+ and the larger Rb+. Encouragingly, the “best model”(mosthighly refined ion parameters, most complete description of solvation) gave the best quantitative reproduction of the experimental free energies. We have also carried out the first example of the calculation of the absolute binding free energy of a macrobicyclic molecule-ion complex. The absolute binding free energy of the calixspherand-Rb" 1" complex was calculated to be-11 to-13 kcal/mol, in good agreement with experiment (-12 to-13 kcal/mol). In addition to reproducing the observed K+ selectivity and shedding light on the experimental free energy data, ion-oxygen radial distribution functions derived from molecular dynamics simulations on the ions, Na+, K+, and Rb+, both in water and in the calixspherand, allowed clear insight into the K+ preference for this calixspherand. Only for K+ does the first peak of the ion-oxygen radialdistribution function in the host coincide with that in water; for Na+, the first peak is at a larger distance in the host than in water; for Rb+, the first peak is at a smaller distance in the host than in water. Both the free energy and structural results further emphasize the delicate balance between ion-water and ion-host interactions that lead to ion selectivity.