Rethinking Ion Transport by Ionophores: Experimental and Computational Investigation of Single Water Hydration in Valinomycin-K Complexes.

Valinomycin is a macrocyclic ionophore that transports K across hydrophobic membranes. Its function depends on selectivity, capture, transport, and release of the ion. While thermodynamics clearly indicate that valinomycin binds K preferentially over all other alkali ions, characterizing the capture/transport/release of K by valinomycin at the molecular level remains a challenge. The bracelet-like structure of valinomycin-K (KVM) has the ion completely enveloped, facilitating transport through the cell membrane. We report that hydration by a single water molecule, (KVM)(HO), produces three different conformers, identified by infrared spectroscopy and supporting computational studies. For two minor conformers, the water prevents the ionophore from closing, a conformation that would inhibit diffusion through the membrane. However, the dominant conformer encloses both the ion and the water, replicating the bracelet-like KVM and arguably enhancing diffusion through the membrane. This potential for active participation of water in transport through the hydrophobic cellular membrane has never been previously considered.