The goal of this research project is to determine the structural basis for the selectivity sequences observed for monocarboxylic acid ionophores and to deduce the mechanisms of complexation and release of ions. Ionophores are antibiotics that induce ion transport across natural and artificial membranes. The resultant changes in transmembrane ion gradients and electric potentials greatly alter cellular function and metabolism thereby influencing a wide spectrum of biological control mechanisms including muscle contraction, stimulus-secretion coupling, mitosis, fertilization, gluconeogenesis and glycogenolysis. The usefulness of ionophores depends upon their ion selectivity and efficiency of transport. A thorough understanding of the molecular basis for selectivity is essential to development of more selective ionophores. In order to achieve these goals X-ray crystallographic structure determinations of judiciously selected complexed and uncomplexed forms of ionophores currently used in medicine and agriculture will be undertaken. A thorough analysis of coordination number, geometric arrangement, bond distances and bond strengths of ions in the selectivity sequences of these ionophores will be made. The extent to which the geometric arrangement of ligand can be adjusted through conformational flexibility associated with cation capture will be determined. Molecular mechanism methods will be used to evaluate the relative energies of the complexed and uncomplexed forms of each ionophore of interest. The structural information obtained will be evaluated in terms of the ion binding strength with empirical methods such as the method of Brown and Shannon. Both the molecular mechanics programs and the bond length, bond strength equations will be further developed for this purpose. Data on molecular structure, molecular flexibility, conformational energy, and coordination bond strength will be used to determine the structural basis for ion selectivity, the mechanisms of ion capture and release, and the influence of chemical modification of the ionophore upon these properties.
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