In the field of science and technology, gold plays an indispensable role due to its special physical and chemical properties. Firstly, gold has particular physical properties such as excellent ductility, electrical and thermal conductivity, and infrared reflectivity, so that it is widely used as a coating for materials or as a conductor and contact in electronic devices. Gold also has unique chemical properties and can be acted as a reaction catalyst or used for the preparation of new drugs. In the recent rise of nanoscience research, gold has been widely used in the preparation of nanostructures and probes. For example, the pregnancy test paper commonly used in our lives is the use of colloidal gold to achieve test reporting. Chloroauric acid (HAuCl4), a well-known Au(III) compound, has been widely used as a precursor for the fabrication of gold nanomaterials, and can interact with proteins and nucleic acid bases. As the limited resolution of instruments, characterization methods such as UV-Vis spectroscopy, mass spectrometry, and NMR spectroscopy are not suitable for in-depth exploration of the dynamic interactions between extremely small analytes, including Au(III) compounds, and biological macromolecules at the single molecule level. Previous reports indicate that Au(III) is a potent aquaporin inhibitor but investigations at the level of a single molecule have not been reported. (FEBS letters, 2002, 531 (3): 443-447). It is necessary to develop available analysis methods to monitor these phenomena more clearly.
Biological nanopore technology is a single-molecule research method with rapid development in recent years, and it has obtained extensive attention in the field of DNA sequencing. However, this remarkable sensing performance originates from its biological role as a channel protein, which is sufficient to resolve small analytes such as metal ions. Pioneered since 1997 by Bayley et al. (Chemistry & biology, 1997, 4(7): 497-505.), nanopore-based direct sensing of single ions such as Co2+, Ag+ or Cd2+ can be performed by designed ion-amino acid coordination or by an ion-chelator interaction within engineered α-hemolysin (α-HL) mutants. However, α-HL blockages by single monatomic ions suffer from an extremely low event amplitude (~2-3 pA), due to the cylindrical pore geometry, the small size of the ionic analyte and possible gating behaviors when monitored at a high voltage. To date, all single-molecule nanoreactors based on biological channels have been constructed from α-HL nanopores.
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Recently, Shuo Huang group unexpectedly discovered that Au(III) ions can bind to the methionine residue (M113) of a wild-type α-hemolysin by reversible Au(III)-thioether coordination. However, the cylindrical pore geometry of α-hemolysin generates shallow ionic binding events (~5-6 pA) and have introduced other undesired interactions, which may result from non-specific binding of Au(III) with other amino acids such as lysine distributed over its long cylindrical restriction. Inspired by nanopore sequencing, a Mycobacterium smegmatis porin A (MspA) nanopore, which possesses a conical pore geometry, is mutated to bind Au(III) ions, and similar current blockade signals were observed (Figure 1,Video 1).
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Figure 1. Binding of [AuCl4]− with methionine (D91M) within an engineered MspA nanopore (MspA-M). (a). A general schematic diagram of [AuCl4]− sensing. (b). A Molecular model display of Au(III)-S coordination. (c).Representative traces with all-points histogram for [AuCl4]− sensing by MspA-M at +100 mV with1 μM HAuCl4 in cis.
Video 1. Representative current traces for [AuCl4]− sensing by MspA-M at +100 mV
Compared to the barrel configuration of α-HL, MspA is a funnel shaped, octameric channel protein. The open vestibule of MspA can introduce more ion current to amplify the event amplitude, and the narrow recognition site provides higher spatial resolution, which greatly weakens the interference of surrounding amino acids. At the maximum detection voltage, further amplified event amplitude, up to ~55 pA, was monitored (Figure 2), it is the largest single ion binding event from a nanopore measurement.
Figure 2. Comparison between WT α-HL and MspA-M for single [AuCl4]− sensing. (a). Geometric comparison between WT α-HL (red) and MspA-M (blue). (b). Representative binding events from a single [AuCl4]− within a WT α-HL or a MspA-M nanopore at+100mV, respectively. (c). Representative traces for [AuCl4]− ions binding in MspA-M at 200 mV. (d) Plot of the mean blockage depth for [AuCl4]− ions in MspA-M and WT α-HL at different voltages.
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When bound to a methionine, the Au(III) atom remains in the proximity of the restriction of MspA for ~0.5 s, forming a transient Au(III) embedment as an adaptor for sensing. Besides the demonstrated Au(III)-thioether interaction, a stronger interaction between Au(III)-thiol is expected, which indicates that an Au(III) embedded MspA may sense a variety of thiol-containing molecules. The most abundant biothiols include L-cysteine (Cys), L-homocysteine (Hcy) and L-glutathione (GSH), which are directly involved in crucial physiological processes. In the experiment, by taking the embedded Au(III) as an atomic bridge, one end of bridge is connected to the thioether on the nanopore and the other end is connected to the free biothiol molecules. Therefore, the current information of biothiols is reported according to its unique reaction intermediate state (Figure 3,Video 2). This sensing mechanism is simple, label free, fast and economic and may be engineered into a portable sensor chip. Moreover, the demonstrated result of Au(III) embedment may benefit a wide range of other fundamental scientific research, such as inspiring the design of drug molecular targets, or designing more metal embedment to construct a series of metal biochannels (Metalloporin) to identify other analytes.
Figure 3.Stochastic sensing of biothiols by Au(III) embedded MspA-M. (a). A molecular model for biothiols sensing. (b). Structure of cysteine, homocysteine, glutathione and corresponding sensor signals.
Video 2. Representative current traces for Cys sensing by Au(III) embedded MspA-M at +100 mV
The work was titled Giant single molecule chemistry events observed from a tetrachloroaurate (III) embedded Mycobacterium smegmatis porin A nanopore, and a related paper was published in Nature Communications on December 11, 2019 (DOI: 10.1038/s41467-019-13677-2, article link: https://www.nature.com/articles/s41467-019-13677-2). Jiao Cao, a phD student in the School of Chemistry and Chemical Engineering, is the first author of the paper, and Prof. Shuo Huang is the corresponding author. The authors would like to thank Academician/Prof. Zijian Guo (Nanjing University), Prof. Jin Zhao (Nanjing University) and Prof. Yuncong Chen (Nanjing University) for inspiring discussions on the coordination chemistry of Au(III) complexes. Prof. Shaolin Zhu (Nanjing University) and Prof. Congqing Zhu (Nanjing University) for inspiring discussions. This work was funded by National Natural Science Foundation of China (Grant No. 91753108, No. 21327902, No.21675083, No. 31972917), Fundamental Research Funds for the Central Universities (Grant No. 020514380142, No. 020514380174), State Key Laboratory of Analytical Chemistry for Life Science (Grant No. 5431ZZXM1804, No. 5431ZZXM1902), Excellent Research Program of Nanjing University (Grant No. ZYJH004), 1000 Plan Youth Talent Program of China, Programs for high-level entrepreneurial and innovative talents introduction of Jiangsu Province. Technology innovation fund program of NanjingUniversity.
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