Walking on the free energy hypersurface of the 18-crown-6 ion system using free energy derivatives

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Abstract
Molecular dynamics simulations have been used to calculate free energy derivatives with respect to nonbonded parameters for both ions and the host, 18‐crown‐6 in cation‐18‐crown‐6 complexes. The free energy derivatives have been used to examine the free energy hypersurface for such complexes and to ‘‘predict’’ the optimal cationic ligand for 18‐crown‐6 complexation in aqueous solution. This method has promise to enable the refinement of the intermolecular interaction parameters for both hosts and guests in aqueous solution. In particular, we show that the optimal ion size for 18‐crown‐6 is calculated to be between the sizes of Na+ and K+, consistent with the experimental data. More generally, it has potential to be a powerful tool in computer aided molecular design.