【JACS】浙江大学黄飞鹤|由分子识别驱动的人工分子换能器：实现厘米级跨相运输与4.8倍反应增强#

文章标题：An Artificial Molecular Transducer Driven by Molecular Recognition
文章作者：Bohan Zhao, Zhongwen Liu, Mingrui Xiao, Mengbin Wang, Shang Li, Enxu Liu, Shiyu Tan, Zhenguo Zhang, Ming Li, Bin Hua, Shuai Fang, J. Fraser Stoddart, Jonathan L. Sessler, Feihe Huang
文章链接：https://doi.org/10.1021/jacs.6c12829

一、研究动因#

自然界中的生物分子机器广泛利用外源信号分子触发受体构象转变以精确调控下游功能。受此启发，人工合成超分子机器（如分子肌肉、电梯与马达）近年来取得了长足发展，但多依赖光、电或酸碱等外部物理化学脉冲作为能源。现有系统的关键短板在于难以模拟生物信号通路的复杂调控机制，尤其是利用特异性刺激响应信号分子实现“由弱到强”的构象门控活化与正交协同识别依然缺乏通用策略。本文旨在构建一种由分子识别直接驱动的模块化人工分子换能器，通过信号分子诱导的构象重组控制小分子客体的结合与释放，从而在人工系统中实现类似跨膜转运的宏观跨相运输与级联生物正交反应。

Scheme 1 Schematic Views of Representative Molecular Machines and the Design Principles at Play in the Present Work Driven by Molecular Recognition#

二、研究实施方案与关键实验结果#

分子设计与作用机理#

研究团队将富电子的柱[5]芳烃单元与缺电子的四阳离子环蕃单元通过共有苯环共价连接，合成了分子换能器。本研究首次提出的核心机制是“分子内自包结锁定与外源信号诱导异构释放”：在初始制备态下，两亚基通过互补静电与芳香堆积发生分子内自包结，使空腔封闭且丧失客体结合能力；当引入外源富电子多环芳烃（如芘、蒽或2,6-蒽二酚）作为信号分子时，其优先占据四阳离子环蕃空腔并置换出柱[5]芳烃，释放出活性结合腔，将客体结合状态由“关”切换至“开”。

Fig.1 Preparation and characterization of the molecular transducer used in this study. (a) Synthetic route to PBox·4PF6. (b) Designed structure and electrostatic potential maps of [PBox]4+. (c) 1H NMR spectrum of PBox·4PF6 in CD3CN at 298 K. (d) Various views of the crystal structure of PBox·4PF6. Solvents and counterions have been removed for clarity.#

Fig.2 Complexation of signaling molecules by the molecular transducer [PBox]4+. (a) Chemical structures of the guests, signaling molecules and proposed mechanism of signal transduction. (b) Partial 1H NMR spectra of (i) PBox·4PF6 (1.00 mM), (ii) PBox·4PF6 (1.00 mM) with S1 (1.00 mM), and (iii) PBox·4PF6 (1.00 mM) with S1 (2.00 mM) in CD3CN at 298 K. Various views of the crystal structures of (c) PBox·4Cl⊃S1 and (d) PBox·4Cl⊃S2. Solvents and counterions have been removed for clarity.#

实验验证与关键性能#

表征体系采用核磁共振、单晶X射线衍射、等温滴定量热（ITC）以及密度泛函理论（DFT）计算。实验表明，未加信号分子时换能器与各客体几乎不结合；引入蒽作为信号分子后，换能器对四氰基苯、双咪唑丁烷、飞蝗聚集信息素苯乙腈及生物正交底物二苯基四嗪的结合常数分别跃升至 $2.31 \times 10^2\ \text{M}^{-1}$ 、 $2.00 \times 10^3\ \text{M}^{-1}$ 、 $1.78 \times 10^2\ \text{M}^{-1}$ 和 $1.08 \times 10^3\ \text{M}^{-1}$ 。利用蒽的紫外光照（300–400 nm）光二聚特性，信号分子在 300 s 内完全二聚脱落并恢复初始自包结态，动力学拟合表观速率常数为 $(1.33 \pm 0.02) \times 10^{-2}\ \text{s}^{-1}$ （半衰期 $52.2\ \text{s}$ ）。

Fig.3 Reversible signal transduction seen with PBox·4PF6 in the presence of appropriately chosen signaling molecules and guests. (a) Partial 1H NMR spectra of (i) PBox·4PF6 (1.00 mM), (ii) PBox·4PF6 (1.00 mM) with S2 (10.0 mM), and (iii) PBox·4PF6 (1.00 mM) with S2 (10.0 mM) after 1200 s of irradiation in CD3CN at 298 K. (b) Visualization of solution state changes induced by the binding and release of S2. (c) Schematic illustration of artificial reversible signal transduction achieved by using PBox·4PF6 with S2 as the signaling molecule and one of G1–G4 as the guest. In its initial state, PBox·4PF6 exhibits weak guest affinity because of intramolecular interactions. (i) Upon introduction of the signaling molecule S2, PBox·4PF6 undergoes a conformational change, which subsequently (ii) enhances its guest-binding ability. (iii) Upon irradiation, S2 is removed from the system, allowing PBox·4PF6 to return to its initial state and thereby (iv) triggering guest release.#

宏观跨相运输与反应级联#

在装有厘米级厚度中间水相的U型管中，换能器成功介导了跨相分子运输。在顺浓度梯度下，光照运行5小时后接收相四氰基苯与苯乙腈浓度分别达 $4.6\ \text{mM}$ 与 $15.8\ \text{mM}$ （未光照对照组接近0）；在初始两侧等浓度的逆浓度梯度测试中，换能器成功克服热力学势垒，实现接收相 $1.1\ \text{mM}$ 的净富集，并可稳定连续循环运行至少4轮。此外，该体系成功驱动二苯基四嗪跨水相与降冰片烯发生反电子需求狄尔斯–阿尔德反应，转化效率较非光照组提升达 4.8倍。

Fig.4 Interphase transport of guests promoted by PBox·4Cl and S3. (a) Schematic view of the down-gradient transport. (b) The concentration of G1 at the receiving phase monitored as a function of time. The blue dots represent data for the test group of G1, while the red dots represent data for the control group. (c) The concentration of G3 at the receiving phase monitored as a function of time. The orange dots represent data for the test group of G3, while the green dots represent data for the control group. (d) Schematic view of the up-gradient transport. (e) Increase in G1 concentration at the receiving phase monitored as a function of time. (f) Schematic view of the transport-enabled reaction based on bioorthogonal chemistry. Initially, G4 serves as the reaction substrate and is located in the source phase. During operation of the molecular transport system, G4 is transported from the source phase across the aqueous solution into the receiving phase, where it reacts with norbornene to form the cascade product.#

三、创新与提升#

本文创新性地建立了基于电子互补双大环共价结合的信号门控分子换能新范式，解决了人工分子机器在信号响应性识别与主动做功上的集成难题。实验证实该体系不仅实现了对多种功能小分子的高亲和力开关调控与高保真可逆复原，更在厘米级尺度下完成了顺/逆浓度梯度的跨相输运及生物正交级联催化放大（4.8倍增强），切实填补了仿生信号传导与宏观功能输出之间的桥梁。研究指出的主要局限为逆浓度运输效率受限于水溶性信号分子的溶解度，未来可通过亲水修饰进一步拓展通量。

【JACS】华东理工杨有军课题组|短波红外四苯并稠合硅罗丹明荧光染料：组织穿透深度（10.9毫米）、曝光时间（50毫秒）、采集时长（10天）及成像对比度（信号背景比大于8）的多方位突破