SELECTIVITY AND MECHANISM OF ACTION OF IONOPHORES

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The goal of this research project is to elucidate the structural principles of ion transport and to establish the main stereochemical criteria which are necessary for construction of shuttle carriers and channels with specified ion selectivity, binding and conducting properties. The chemical and geometric features which characterize ion selective organic transport ligands are to be examined in greater detaiL The efficient transport of ions does not simply depend on a high binding affinity of channel or shuttle ligands for specific ions at the solvent/lipid interface of the ion-rich side of the membrane, but also on a facilitated mechanism of ion release on the distal side of the membrane which permits the channel or the ligand shuttle to eject an ion so it can recycle back to the ion-rich side of the membrane. The series of newly synthesized valinomycin, cyclo-[D-Val-L-Lac-L-Val-D- Hyi)3-], analogues are to be examined to test a number of hypotheses concerning the flexibility with which the uncomplexed ionophore may wrap around and chelate metals of different atomic radii and ionic charge. This series includes six (DLLD)3 stereoregular cyclo-dodecadepsipeptide analogues which substitute Gly for D-Val and L-Ala, L-Pro, L-Glu or L- Glu(OBzlNO2) for L-Val in various single or multiple position sites of the normal valinomycin sequence. One unusually interesting analogue which has an (LLLD)-(DLDD)(DLLD) altered stereoregular sequence of valine and hydroxyisovaleric acid residues is also to be investigated. These ligand analogues are to be crystallized in the uncomplexed form as well as complexed with various sized and charged ions in different chemical solvents. Studies of the channel forming ionophore gramicidin A in free and various complexed forms with alkaline cations will be expanded to new crystal forms obtained from different pure solvents and their mixtures. Different polymorphs of all compounds under study will be extensively examined by X-ray diffraction, molecular mechanics and computer graphics methods to explore the conformational space of these agents for elucidation of the molecular mechanism of their functioning and design new analogs with predetermined properties.