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。电离团 是诱导离子跨天然和人工转运的抗生素吗？ 膜。由此产生的跨膜离子梯度和 电位极大地改变了细胞的功能和新陈代谢。 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。电离团的用处取决于 取决于它们的离子选择性和传输效率。一次彻底的 了解选择性的分子基础对于 开发更具选择性的电离团。 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。 深入分析了配位数、几何图形的差异 配位氧、键距离和键强度的安排 这些离子载体的选择性序列中的离子将被制成。 配体的几何排列可以达到的程度 通过构象灵活性调整的电离团将是 下定决心。未络合形式的结构的确定 Gramicidin A，一种线状肽，被认为形成一种通道， 许可一价阳离子的选择性膜转移将是 将一系列新开发的直接方法应用于 最近在125摄氏度收集的极好的强度数据集。 将使用分子力学方法来评估相对能量。 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、构象能和键 强度将被用来确定离子的结构基础 选择性，离子捕获和释放的机制，并建议 对离子载体的化学修饰，从而改变其性质。

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 the 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 the differences in coordination number, geometric arrangement of coordinating oxygens, bond distances and bond strengths to the ions in the selectivity sequences of these ionophores will be made. The extent to which the geometric arrangement of the ligands can be adjusted through conformational flexibility of the ionophores will be determined. The determination of the structure of uncomplexed forms of gramicidin A, a linear peptide that is presumed to form a channel that permits selective membrane transfer of monovalent cations will be undertaken applying a battery of newly developed direct methods to an excellent intensity data set recently collected at 125 Degree K. Molecular mechanics 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 bond strengths which will be used to determine the structural basis for ion selectivity, the mechanisms of ion capture and release, and to suggest chemical modifications of the ionophore which alter their properties.