Ion-selective properties of a small ionophore in methanol studied by free energy perturbation simulations

The ion-selective properties of the cyclic depsipeptide molecule valinomycin in methanol are studied by free energy perturbation molecular dynamics simulations. The dependence of the alkali cation selectivity on the dipole moment of the backbone carbonyl groups that ligate the ion is examined and found to behave in a systematic way. Since available force fields have not been parametrized for this type of ion-carbonyl interaction, the results are used to determine carbonyl partial charges that reproduce the observed selectivity quantitatively. The optimal dipole moment is somewhat higher than that normally used in molecular mechanics force fields and indicates that there is a significant polarization of the carbonyl groups by the field from the ion The simulations also suggest that the unloading of ions mainly would occur through the lactic acid face of the molecule since it does not provide as effective a shield against attack from the solvent as the more hydrophobic isohydroxyvaleri