SELECTIVITY AND MECHANISM OF ACTION OF IONOPHORES

本研究项目的目标是确定结构基础， 观察到的单羧酸离子载体的选择性序列， 以推断离子络合和释放的机理。 离子载体是抗生素，其诱导离子跨天然和天然环境的运输。 人造膜 跨膜离子梯度的变化 和电位极大地改变了细胞功能和新陈代谢 从而影响广泛的生物控制机制 包括肌肉收缩、刺激-分泌偶联、有丝分裂 受精、胚胎发育和糖原分解。 离子载体的有用性取决于它们的离子选择性， 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离子载体至关重要。 为了实现这些目标，X射线晶体结构 确定明智选择的复合和非复合形式的 目前用于医学和农业的离子载体将被研究。 对配位数、几何排列、成键进行了深入分析 这些选择性序列中离子的距离和键强度 将产生离子载体。 几何排列的程度 配体可以通过与以下相关的构象柔性来调节： 将测定阳离子捕获。 分子机理方法将被用来评估相对能量 每种感兴趣的离子载体的复合和未复合形式。 的 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，如布朗的方法， 香农 分子力学程序和键长，键 将为此目的进一步发展强度方程。 数据 分子结构，分子柔性，构象能，和 配位键强度将用于确定结构基础 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.