Fachbereich Chemie, Philipps-Universität Marburg , Hans Meerwein Strasse, 35032 Marburg, Germany.
Acc Chem Res. 2013 Dec 17;46(12):2773-80. doi: 10.1021/ar400007w. Epub 2013 May 7.
Ion channels provide a conductance pathway for the passive transport of ions across membranes. These functional molecules perform key tasks in biological systems such as neuronal signaling, muscular control, and sensing. Recently, function-oriented synthesis researchers began to focus on ion channels with the goal of modifying the function of existing ion channels (ion selectivity, gating) or creating new channels with novel functions. Both approaches, ion channel engineering and de novo design, have involved synthetic chemists, biochemists, structural biologists, and neurochemists. Researchers characterize the function of ion channels by measuring their conductance in samples of biological membranes (patch clamp) or artificial membranes (planar lipid bilayers). At the single molecule level, these measurements require special attention to the purity of the sample, a challenge that synthetic chemists should be aware of. Ideally, researchers study the function of channels while also acquiring structural data (X-ray, NMR) to understand and predict how synthetic modifications alter channel function. Long-term oriented researchers would like to apply synthetic ion channels to single molecule sensing and to implantat these synthetic systems in living organisms as tools or for the treatment of channelopathies. In this Account, we discuss our own work on synthetic ion channels and explain the shift of our research focus from a de novo design of oligo-THFs and oligo-THF-amino acids to ion channel engineering. We introduce details about two biological lead structures for ion channel engineering: the gramicidin β(6,3) helix as an example of a channel with a narrow ion conductance pathway and the outer membrane porins (OmpF, OmpG) with their open β-barrel structure. The increase and the reversal of ion selectivity of these systems and the hydrophobic match/mismatch of the channel with the phospholipid bilayer are of particular interest. For engineering ion channels, we need to supplement the single-point attachment of a synthetic modulator with the synthesis of a more challenging two-point attachment. The successful function-oriented synthesis of ion channels will require interdisciplinary efforts that include new electrophysiology techniques, efficient synthesis (peptide/protein/organic), and good structural analysis.
离子通道为离子穿过细胞膜的被动运输提供了电导途径。这些功能分子在生物系统中执行关键任务，如神经元信号传递、肌肉控制和感知。最近，面向功能的合成研究人员开始关注离子通道，目标是修饰现有离子通道的功能（离子选择性、门控）或设计具有新功能的新通道。这两种方法，离子通道工程和从头设计，都涉及到合成化学家、生物化学家、结构生物学家和神经化学家。研究人员通过测量生物膜（膜片钳）或人工膜（平面脂质双层）样品中的电导来表征离子通道的功能。在单分子水平上，这些测量需要特别注意样品的纯度，这是合成化学家应该注意的一个挑战。理想情况下，研究人员在研究通道功能的同时还获取结构数据（X 射线、NMR），以了解和预测合成修饰如何改变通道功能。长期研究人员希望将合成离子通道应用于单分子传感，并将这些合成系统植入生物体中作为工具或用于治疗通道病。在本综述中，我们讨论了我们自己在合成离子通道方面的工作，并解释了我们的研究重点从从头设计寡聚四氢呋喃和寡聚四氢呋喃-氨基酸转移到离子通道工程的转变。我们介绍了两个用于离子通道工程的生物先导结构的详细信息：作为具有狭窄离子导电路径的通道的革兰氏杀菌素β（6,3）螺旋的例子和具有开放β-桶结构的外膜孔蛋白（OmpF、OmpG）。这些系统的离子选择性的增加和反转以及通道与磷脂双层的疏水性匹配/不匹配特别有趣。对于工程离子通道，我们需要用更具挑战性的两点连接合成来补充合成调节剂的单点连接。离子通道的成功功能导向合成将需要包括新的电生理学技术、高效合成（肽/蛋白质/有机）和良好的结构分析在内的跨学科努力。
