SELECTIVITY AND MECHANISM OF ACTION OF IONOPHORES

这项研究项目的目标是确定 观察到的单羧酸离子载体的选择性序列和 推测离子的络合和释放机理。 离子载体是一种抗生素，可以诱导离子在天然和非生物环境中的传输 人造薄膜。由此产生的跨膜离子梯度的变化 电势极大地改变了细胞的功能和新陈代谢 从而影响广泛的生物防治机制 包括肌肉收缩，刺激-分泌耦合，有丝分裂， 受精、糖异生和糖原分解。 离子载体的有用性取决于它们的离子选择性和 运输效率。对分子基础的透彻理解 因为选择性对于开发更具选择性的电离团是必不可少的。 为了实现这些目标，X射线晶体结构 对审慎选择的复杂和非复杂形式的确定 将开展目前用于医药和农业的电离团。 对配位数、几何构型、键的深入分析 它们的选择性序列中离子的距离和键强度 电离团将被制造出来。几何排列的程度 配基可以通过构象灵活性进行调节 阳离子捕获量将被测定。 分子机理方法将被用来评估相对能量 每个感兴趣的电离团的复杂和非复杂形式。这个 获得的结构信息将根据离子进行评估 结合强度与经验方法，如Brown和 香农。分子力学程序和键长、键 为此，将进一步发展强度方程。数据在 分子结构、分子柔性、构象能和 将使用协调键强度来确定结构基础 对于离子选择性，离子捕获和释放的机制，以及 离子载体的化学修饰对这些性质的影响。

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.