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，诱导离子运输通过天然和人工 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功能和新陈代谢， 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， 糖原分解。 离子载体的效用取决于 取决于它们的离子选择性和传输效率。 的透彻 了解选择性的分子基础对于 开发更有选择性的离子载体。 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。 深入分析了配位数、几何 配位氧的排列、键距和键强度， 将产生这些离子载体的选择性序列中的离子。 配体的几何排列可以被改变的程度 通过离子载体的构象灵活性进行调节， 测定 非络合形式的结构测定 短杆菌肽A是一种线性肽，据推测可形成通道， 允许一价阳离子的选择性膜转移， 采用一系列新开发的直接方法， 最近在125开氏度收集到的一组极好的强度数据。 分子力学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、构象能和键 将用于确定离子的结构基础的强度 选择性，离子捕获和释放的机制，并建议 离子载体的化学修饰改变了它们的性质。

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.