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Self-Assembling Organic Nanopores as Synthetic Transmembrane Channels with Tunable Functions.

机译：自组装有机纳米孔作为具有可调功能的合成跨膜通道。

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摘要

A long-standing goal in the area of supramolecular self-assembly involves the development of synthetic ion/water channels capable of mimicking the mass-transport characteristics of biological channels and pores. Few examples of artificial transmembrane channels with large lumen, high conductivity and selectivity are known. A review of pronounced biological transmembrane protein channels and some representative synthetic models have been provided in Chapter 1, followed by our discovery and initial investigation of shape-persistent oligoamide and phenylene ethynylene macrocycles as synthetic ion/water channels.;In Chapter 2, the systematic structural modification of oligoamide macrocycles 1, the so-called first-generation of these shape-persistent macrocycles, has led to third-generation macrocycles 3. The third generation was found to exhibit unprecedented, strong intermolecular association in both the solid state and solution via multiple techniques including X-ray diffraction (XRD), SEM, and 1H NMR. Fluorescence spectroscopy paired with dynamic light scattering (DLS) revealed that macrocycles 3 can assemble into a singly dispersed nanotubular structure in solution.;The resultant self-assembling pores consisting of 3 were examined by HPTS-LUVs assays and BLM studies (Chapter 3) and found to form cation-selective (PK+/PCl- = 69:1) transmembrane ion channels with large conductance (200 ∼ 2000 pS for alkali cations) and high stability with open times reaching to 103 seconds. Tuning the aggregation state of macrocycles by choosing an appropriate polar solvent mixture (i.e., 3:1, THF:DMF, v/v) and concentration led to the formation of ion channels with well-defined square top behavior. A parallel study using DLS to examine the size of aggregates was used in conjunction with channel activity assays (LUVs/BLM) to reveal the effects of the aggregation state on channel activity. Empirical evidence now clearly indicates that a preassembled state, perhaps that of a nanotubular assembly, rather than the individual molecules of 3, is required to partition into the lipid bilayer in order for these macrocycles to act as channels.;Further structural modification has led to fourth-generation macrocycles 4 having readily-tunable cavities (Chapter 4). Macrocycles 4 , with a hybrid backbone composed half of the oligoamide and half of the phenylene ethynylene moieties, exhibits similar self-assembling behavior by forming nanotubular stacks. The results of a preliminary study based on LUVs-assays and BLM single channel recording experiments are summarized and clearly indicate that ion channels formed by this fourth-generation exhibit high stability and differing ion selectivity largely consistent with the corresponding structural modification of the interior cavity. Especially, the increased anion conductance observed for 4d indicates that our strategy of tuning supramolecular function based on synthetic modification of the backbone and pore is effective.;In Chapter 5, our four-residue tetraurea macrocycles 5 have shown significant potency to selectively interact with the G-quadruplex, leading to a strong stabilization effect for G-quadruplex without binding to duplex DNA as observed by UV-melt assays. The ready synthetic availability of these macrocycles makes them amenable to future chemical modification, which allows systematic improvement of binding affinity and specificity. Moreover, it has been discovered that these macrocycles can partition into lipid bilayers and form very stable transmembrane ion channels with a pore size of ∼5 A. Preliminary data shows that this smaller ion channel may lead to exceptional ion conducting selectivity, which is rarely seen in the field of synthetic ion pores. These molecules may serve as a unique platform for the rational development of potent and versatile therapeutic agents.;The exceptional ion conducting properties of these channels place aromatic oligoamide macrocycles 3 and 4 at a unique position with both high conductance and long channel-opening duration. These results demonstrate that oligoamide macrocycles provide us a reliable platform based on which further development of highly conducting and selective synthetic mass-transporting channels, with functions that are comparable to or even rival those of natural channels and pores, may be developed. Further improvement of these synthetic channels could lead to numerous applications, such as those for complementing ion channel deficiency in clinical medicine, designing biosensors, and the development of new materials, as well as their use in separation and purifications.
机译：超分子自组装领域的长期目标涉及开发能够模拟生物通道和孔的质量传输特性的合成离子/水通道。具有大内腔，高电导率和选择性的人工跨膜通道的例子很少。第1章对明显的生物跨膜蛋白通道和一些代表性的合成模型进行了综述，随后我们发现并初步研究了形状持久性低聚酰胺和亚苯基乙炔基大环作为合成离子/水通道。低聚酰胺大环1的结构修饰，即所谓的这些形状持久性大环的第一代，已导致第三代大环3。发现第三代在固态和溶液中均表现出前所未有的强分子间缔合多种技术，包括X射线衍射（XRD），SEM和1H NMR。荧光光谱与动态光散射（DLS）配对显示，大环3可以在溶液中组装成单个分散的纳米管结构;通过HPTS-LUVs分析和BLM研究（第3章）检查了由3个组成的自组装孔发现形成具有高电导率（碱金属阳离子为200〜2000 pS）和高稳定性的阳离子选择性（PK + / PCl- = 69：1）跨膜离子通道，打开时间可达103秒。通过选择适当的极性溶剂混合物（即3：1，THF：DMF，v / v）和浓度来调节大环的聚集状态，并导致形成具有明确定义的方顶行为的离子通道。平行研究使用DLS检查聚集体的大小，并与通道活性测定法（LUVs / BLM）结合使用，以揭示聚集状态对通道活性的影响。现在的经验证据清楚地表明，为了使这些大环充当通道，需要预先组装的状态（也许是纳米管组装的状态，而不是单个3的分子）分配到脂质双层中;进一步的结构修饰导致腔易于调整的第四代大循环4（第4章）。具有杂化骨架由一半的低聚酰胺和一半的亚苯基乙炔基组成的大环化合物4通过形成纳米管叠层而表现出相似的自组装行为。总结了基于LUV分析和BLM单通道记录实验的初步研究结果，这些结果清楚地表明，第四代形成的离子通道显示出高稳定性，并且不同的离子选择性与内部腔体的相应结构修饰基本一致。特别是，在4d观察到的增加的阴离子电导表明，我们基于骨架和孔的合成修饰来调节超分子功能的策略是有效的。在第5章中，我们的四残基四脲大环化合物5具有显着的选择性与四氢呋喃相互作用的能力。 G-四链体，导致G-四链体具有很强的稳定作用，而不会与双链体DNA结合，如UV熔解法所观察到的。这些大环化合物现成的合成可用性使其适合将来的化学修饰，从而可以系统地改善结合亲和力和特异性。此外，已发现这些大环化合物可划分为脂质双层，并形成孔径约为5 A的非常稳定的跨膜离子通道。初步数据表明，该较小的离子通道可能导致异常的离子传导选择性，这很少见在合成离子孔领域。这些分子可作为合理开发有效和多功能治疗剂的独特平台。这些通道的卓越离子传导特性将芳香族寡酰胺大环3和4置于具有高电导率和长通道开放时间的独特位置。这些结果表明，低聚酰胺大环化合物为我们提供了一个可靠的平台，在此基础上，可以开发出与天然通道和毛孔相比甚至更高的功能的高传导性和选择性合成传质通道。这些合成通道的进一步改进可能会导致许多应用，例如用于弥补临床医学中离子通道不足，设计生物传感器，开发新材料以及将其用于分离和纯化的应用。

著录项

  • 作者

    Wei, Xiaoxi.;

  • 作者单位

    State University of New York at Buffalo.;

  • 授予单位 State University of New York at Buffalo.;
  • 学科 Nanoscience.;Chemistry Organic.
  • 学位 Ph.D.
  • 年度 2014
  • 页码 185 p.
  • 总页数 185
  • 原文格式 PDF
  • 正文语种 eng
  • 中图分类
  • 关键词

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