SELECTIVITY AND MECHANISM OF ACTION OF IONOPHORES

本研究项目的目标是阐明 离子传输原理，并建立主要的立体化学 建造穿梭运输车所需的标准， 具有特定离子选择性、结合和传导的通道 特性.表征离子的化学和几何特征 选择性有机转运配体将被更详细地研究。 离子的有效传输并不简单地依赖于高结合 通道或穿梭配体对特定离子的亲和力 溶剂/脂质界面的膜的离子丰富的一面，但也对 在膜的远端侧上的离子释放的促进机制 其允许通道或配体穿梭器喷射离子， 再循环回到膜的富离子侧。 本文报道了新合成的缬氨霉素系列化合物cyclo-[D-Val-L-Lac-L-Val-D-Lac]， Hyi）3-]，类似物将被检查，以测试一些假设 关于未复合的离子载体可以包裹的柔性 并螯合不同原子半径和离子电荷的金属。这 系列包括六个（DLLD）3立体规则的环十二缩酚肽 用Gly取代D-Val和L-Ala、L-Pro、L-Glu或L-Glu的类似物 Glu（OBzlNO 2）替换L-Val的多个单个或多个位置位点中的L-Val。 正常缬氨霉素序列。一个非常有趣的类比， 缬氨酸的（LLLD）-（DLDD）（DLLD）改变的有规立构序列，和 还将研究羟基异戊酸残基。这些配体 类似物将以未络合的形式结晶， 在不同的化学物质中与各种大小和电荷的离子络合， 溶剂. 离子载体短杆菌肽A在游离和不同浓度下形成通道的研究 与碱性阳离子的络合形式将扩展为新的晶体 从不同的纯溶剂及其混合物中获得的形式。 研究中的所有化合物的不同多晶型物将被广泛地 通过X射线衍射、分子力学和计算机图形学进行检测 方法来探索这些代理的构象空间， 阐明其功能的分子机制，并设计新的 具有预定属性的类似物。

The goal of this research project is to elucidate the structural principles of ion transport and to establish the main stereochemical criteria which are necessary for construction of shuttle carriers and channels with specified ion selectivity, binding and conducting properties. The chemical and geometric features which characterize ion selective organic transport ligands are to be examined in greater detaiL The efficient transport of ions does not simply depend on a high binding affinity of channel or shuttle ligands for specific ions at the solvent/lipid interface of the ion-rich side of the membrane, but also on a facilitated mechanism of ion release on the distal side of the membrane which permits the channel or the ligand shuttle to eject an ion so it can recycle back to the ion-rich side of the membrane. The series of newly synthesized valinomycin, cyclo-[D-Val-L-Lac-L-Val-D- Hyi)3-], analogues are to be examined to test a number of hypotheses concerning the flexibility with which the uncomplexed ionophore may wrap around and chelate metals of different atomic radii and ionic charge. This series includes six (DLLD)3 stereoregular cyclo-dodecadepsipeptide analogues which substitute Gly for D-Val and L-Ala, L-Pro, L-Glu or L- Glu(OBzlNO2) for L-Val in various single or multiple position sites of the normal valinomycin sequence. One unusually interesting analogue which has an (LLLD)-(DLDD)(DLLD) altered stereoregular sequence of valine and hydroxyisovaleric acid residues is also to be investigated. These ligand analogues are to be crystallized in the uncomplexed form as well as complexed with various sized and charged ions in different chemical solvents. Studies of the channel forming ionophore gramicidin A in free and various complexed forms with alkaline cations will be expanded to new crystal forms obtained from different pure solvents and their mixtures. Different polymorphs of all compounds under study will be extensively examined by X-ray diffraction, molecular mechanics and computer graphics methods to explore the conformational space of these agents for elucidation of the molecular mechanism of their functioning and design new analogs with predetermined properties.