WALKING ON THE FREE-ENERGY HYPERSURFACE OF THE 18-CROWN-6 ION SYSTEM USING FREE-ENERGY DERIVATIVES

Molecular dynamics simulations have been used to calculate free energy derivatives with respect to nonbonded parameters for both ions and th e host, 18-crown-6 in cation-18-crown-6 complexes. The free energy der ivatives have been used to examine the free energy hypersurface for su ch complexes and to ''predict'' the optimal cationic ligand for 18-cro wn-6 complexation in aqueous solution. This method has promise to enab le the refinement of the intermolecular interaction parameters for bot h hosts and guests in aqueous solution. In particular, we show that th e optimal ion size for 18-crown-6 is calculated to be between the size s of Na+ and K+, consistent with the experimental data. More generally , it has potential to be a powerful tool in computer aided molecular d esign.