Membrane-Active Molecular Machines.
Membrane-Active Molecular Machines.
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DOI：
10.1021/acs.accounts.1c00804
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发表时间：
2022-03
影响因子：
18.3
通讯作者：
Jie Shen;Changliang Ren;H. Zeng
中科院分区：
文献类型：
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作者：
Jie Shen;Changliang Ren;H. Zeng
概述生物膜转运蛋白和人工膜转运蛋白主要通过通道或载体机制介导被动跨膜离子通量，严格调节进出细胞的物质的运输。 Smith 报道了一个无法分类为载体或通道的早期优雅例子，他将磷脂分子衍生为阴离子转运蛋白，通过两站中继机制促进膜转运（Smith 等人 J. Am. Chem. Soc. 2008, 130, 17274-17275）。我们模糊甚至打破载体和渠道机制界定的界限的旅程始于 2018 年 1 月，当时看到一个孩子在游乐场公园的秋千上荡秋千。从那时起，我一直想知道我们是否可以构建一个纳米级的分子摆动装置，能够在分子水平上执行摆动功能，以诱导跨膜离子通量。这种研究之旅在几种膜活性人工分子机器中达到了顶峰，包括分子摆动器、离子捕捞器、离子游泳器、转子、四足动物和十二角动物，它们分别通过摆动、离子钓鱼、游泳、旋转或摆动中继动作使膜透化。除了分子离子游泳者之外，这些非常规膜转运蛋白在最稳定的状态下很容易以类似于通道的方式跨越整个膜。它们具有可在动态膜环境中摆动或弯曲的内置柔性臂，通过不断变化的离子渗透路径传输离子，这些路径比载体更明确，但比通道更不明确。然而，这些转运蛋白采用相同的苯并冠醚基团作为唯一的离子结合和传输单元，但在离子传输特性方面存在巨大差异。虽然最大的 K+ 转运活性是通过分子摆动（也称为“运动通道”）实现的，该分子摆动的 EC50 值为相对于脂质的 0.021 mol%，并且转运 K+ 离子的速率比短杆菌肽 A 快 27%，但分子离子 Fisher 实现了最高的 K+/Na+ 选择性 18.3，分子 dodecapus 的最高 Na+/K+ 选择性为 13.7。分子转子和四形体的 EC50 值为 0.49-1.60 mol%，K+/Na+ 值为 1.1-6.3，通常具有活性，但具有弱到中度的 K+ 选择性。对于含有 10 至 14 个碳原子烷基连接体的分子离子游动蛋白，它们都是高活性 (EC50 = 0.18-0.41 mol %) 和高选择性 (RK+/RNa+ = 7.0-9.5) 的转运蛋白。特别值得注意的是冠醚附加的分子十二角，它将C60-富勒烯核心建立为一个优秀的平台，允许溶液结合亲和力直接转化为跨膜离子传输选择性，为合理设计具有高传输选择性的人工离子转运蛋白提供了从头基础。考虑到分子摆动和离子游泳者表现出的显着细胞毒性活性，各种类型的现有和新兴的非常规膜转运蛋白具有增强的活性和选择性，最终可能会在未来带来医疗益处。
ConspectusBoth biological and artificial membrane transporters mediate passive transmembrane ion flux predominantly via either channel or carrier mechanisms, tightly regulating the transport of materials entering and exiting the cell. One early elegant example unclassifiable as carriers or channels was reported by Smith who derivatized a phospholipid molecule into an anion transporter, facilitating membrane transport via a two-station relay mechanism (Smith et al. J. Am. Chem. Soc. 2008, 130, 17274-17275). Our journey toward blurring or even breaking the boundaries defined by the carrier and channel mechanisms starts in January of 2018 when seeing a child swinging on the swing at the playground park. Since then, I have been wondering whether we could build a nanoscale-sized molecular swing able to perform the swing function at the molecular level to induce transmembrane ion flux. Such research journey culminates in several membrane-active artificial molecular machines, including molecular swings, ion fishers, ion swimmers, rotors, tetrapuses and dodecapuses that permeabilize the membrane via swinging, ion-fishing, swimming, rotating, or swing-relaying actions, respectively. Except for molecular ion swimmers, these unconventional membrane transporters in their most stable states readily span across the entire membrane in a way akin to channels. With built-in flexible arms that can swing or bend in the dynamic membrane environment, they transport ions via constantly changing ion permeation pathways that are more defined than carriers but less defined than channels. Applying the same benzo-crown ether groups as the sole ion-binding and -transporting units, these transporters however differ immensely in ion transport property. While the maximal K+ transport activity is achieved by the molecular swing also termed "motional channel" that displays an EC50 value of 0.021 mol % relative to lipid and transports K+ ions at rate 27% faster than gramicidin A, the highest K+/Na+ selectivity of 18.3 is attained by the molecular ion fisher, with the highest Na+/K+ selectivity of 13.7 by the molecular dodecapus. Having EC50 values of 0.49-1.60 mol % and K+/Na+ values of 1.1-6.3, molecular rotors and tetrapuses are found to be generally active but weakly to moderately K+-selective. For molecular ion swimmers that contain 10 to 14 carbon atom alkyl linkers, they all turn out to be highly active (EC50 = 0.18-0.41 mol %) and highly selective (RK+/RNa+ = 7.0-9.5) transporters. Of special note are crown ether-appended molecular dodecapuses that establish the C60-fullerene core as an excellent platform to allow for a direct translation of solution binding affinity to transmembrane ion transport selectivity, providing a de novo basis for rationally designing artificial ion transporters with high transport selectivity. Considering remarkable cytotoxic activities displayed by molecular swings and ion swimmers, the varied types of existing and emerging unconventional membrane transporters with enhanced activities and selectivities eventually might lead to medical benefits in the future.