Single Pore Sensing
Single Pore Sensing is ... (lead goes here, see other articles for examples)
Viral DNA Packaging Motor for Single Pore Sensing
Overview
Viral DNA packaging motor
Viral genomes are stored within a protein shell known as a capsid. In the final stage of replication and morphogenesis, double-stranded (ds) DNA viruses, e.g., Phi29[1], use a nanomotor to package their genomes into a preformed procapsid or prohead for bacteriophages. Viral genomes are enclosed in a protein shell called a capsid[2]. Once synthesized by separate machinery, viral structural proteins and their genetic material interact, forming a virion in a process titled DNA or RNA packaging, respectively. All linear dsDNA or dsRNA viruses, dsDNA and dsRNA bacteriophages,[3][4][5] adenoviruses[6], poxviruses[7] and herpes simplex viruses (HSV)[8] contain a conserved feature amongst them: a preformed procapsid. The process is entropically unfavorable and therefore requires energy in the form of ATP to drive this packaging motor.[9]
Structure and Function of the motor channel, the connector, as nanopore
Phi29 Connector: The connector is comprised of 12 proteins (36kDa each) forming a ring structure with a blunted cone on both ends. Each unit that comprises the ring is 36kDa in weight. The ring itself has two ends, one denoted as an N-terminal (6.6nm in diameter) and the other as a C-terminal (13.8nm in diameter). The diameter of the channel formed within the ring is ~3.6nm. The channel itself has a unique property in that translocation (movement of materials) of dsDNA during the packaging phase of the organism is unidirectional, N to C-terminal.[10] The phi29 DNA-packaging nanomotor (Fig. 1) is one of the most robust biological motors known.
SPP1 Connector: The connector is comprised of four domains: clip, stem, and wing.[11] Thirteen proteins combine to form a cone structure with a final weight of 745kDa. The connector is roughly 16.5nm across and 11nm in height; the interior region constricts to 2.7nm.[12]
T3 Connector: The connector can be comprised of 12 to 13 subunits of Gp8 (Gp, Glycoprotein) depending on environmental conditions and genetic factors.[13][14][15] The 12 unit connector has been found to have a height of 8.5nm, width of 14.9nm and an internal diameter of 3.7nm.
T4 Connector: This connector is comprised of 12 subunits which, once connected, form a dodecameric ring with a weight of ~660kDa. The connector has so far been observed to have a length of 12nm, an external diameter ranging from 8 to 17nm and an internal diameter of ~2.8nm.[16][17][18][19][20][21][22][23][24]
P22 Connector: The connector is comprised of 11 or 12 subunits of Gp1 with a molecular weight of roughly 940kDa.[25][26][27] The internal diameter of this connector can range from 2.5 to 4nm. This connector contains a unique feature known as an alpha-helical barrel domain which makes this connector readily available for DNA translocation.[28][29][30][31][32]
T7 Connector: This connector is formed from 12 subunits to give it a total molecular weight of 708kDa.[33][34][35][36] The connector has been described as 13.1nm in length, 5.9 to 17.3nm and 3.9nm in its external and internal diameters, respectively. It also contains lysine residues within the stem domain which allows for increased favorability in DNA translocation.[37][38]
HK97 Connector: The connector consists of 13 subunits, known as Gp6, and belongs to the family of phages described as Long-Tailed. The interior and exterior diameter dimensions are 3.7 and 11.4nm. The Gp6 subunits that comprise it contain four long α-helices and two β-strands.
Bacteriophage λ Connector: This connector is comprised of proteins gpW and gpFII.[39][40]
Principle of Single Pore Sensing
Single Pore Sensing can be readily described by its name: insertion of a singular biological nanopore into a membrane for the purpose of sensing polynucleotides or proteins, all with or without chemical modifications. Since its conception in the 1980s with the first demonstration of its potential by Kasianowicz et al., the researchers were able to definitively show that ssRNA and ssDNA (ss – Single Stranded) could be translocated or moved through an α-Hemolysin nanopore.[41]. During the past 2 decades, scientists have improved upon insertion techniques and the variety of pores to be inserted. Recent interest has been devoted to using bacteriophage nanopores to improve upon the limitations from α-Hemolysin. However, some features have remained constant throughout the development process, such as usage of a Lipid Bilayer Membrane and electrical currents to drive the analytes through the inserted nanopore. Some of the most prominently used nanopores have been α-Hemolysin, Aerolysin, and Phi29.[42] The crucial feature in the use of all these nanopores has been the diameter of their inner channel: Aerolysin with 2.6 nm, α-Hemolysin with 1.2 nm, and Phi29 with 3.6 nm.[43] The Phi29 and Aerolysin connectors with an inner channel diameter above 2nm, the diameter of dsDNA, make them more amenable to a variety of uses in Single Pore Sensing.
Once an electrical current is applied in a system with an inserted nanopore, a variety of molecules from DNA and RNA to chemicals and peptides can be translocated. This translocation of any molecule will in turn generate a distinct fingerprint in the baseline electrical current.[44][45][46][47] The fingerprint electrical signal left by these can be described by their current blockage size and dwell time.[48][49][50]
Biological nanopore sensing has arisen from the idea of the resistive pulse technique.[51][52] In summary, a connector is inserted into a lipid bilayer membrane, forming the nanopore channel. In this complex housed within a solution are ions that are able to freely cross the resulting channel as a constant voltage is applied; thus generating a baseline current given in amperes. Each nanopore has a specific amperage at a given voltage, thus allowing for certainty as to whether the nanopore is fully inserted. When analytes are introduced into this nanopore channel, there is a disruption of this ion flow resulting in a shift in the current. This shift in amperage is what generates a fingerprinting signal unique to the analyte; these factors that are needed for identification are current blockage and dwell time. Current blockage is defined as the percentage of the current that is blocked when compared to the previously open current. Dwell time is then defined as the length of the current blockage.
As the analytes are driven through the nanopore or come into contact with it, there are a variety of factors that can affect current blockage and dwell time,[49] i.e., the analytes' shape, length, charge, hydrophobicity or hydrophilicity, or the changes to the connector itself.[53][54][55][56] Analytes with a smaller diameter than the nanopore that are readily able to translocate through it and generate a wide variety of fingerprints due to the various points for interaction as it passes through the pore; e.g., longer chains on an analyte will generate a longer dwell time when compared to their counterparts.[57][48][58][59] Analytes with a diameter larger than the connector still interact with it but only externally or briefly on the top of the internal channel; this external interaction can actually generate a conformational change to the connector, which can also have a different dwell time.[60][61]
Application
Detection of Macromolecules such as DNA, RNA and Peptides
The characteristics distinct to each molecule, whether it be a nucleotide to amino acid chain, will give off a unique electrical signal allowing for detection and classification as they translocate.[62][63][64] This has further been shown by various researchers offering up evidence of their detection and differentiation of proteins, peptides, DNA and RNA.[65] [66][67][68][69][60][70][71] Even peptides of various lengths have been discerned via this method with the knowledge that increased peptide size will increase blockage motif size and dwell time.[72] The Single-Molecule Pore Sensing technique has been recently shown as a versatile tool with its ability for single-molecule detection with increased sensitivity and specificity, all while offering real-time identification, a requisite of only a small sample size (microliters) and concentration (nano- or pico-molar).[73]
Detection Chemicals
Research has shown that Single Pore Sensing systems are capable of detecting a variety of chemicals; this is wholly dependent upon what modifications have been made to the connectors. This detection is very similar to how one would detect the DNA or protein analytes; distinct electrical signals and motifs are generated when the electrical current is disrupted via physical blocking.[66][67][68][69][60]
Single Pore Sensing is readily applicable for medical bio- and nano-technological needs.[74] Researchers have recently developed a novel method for detecting and fingerprinting proteins that are larger than the inner channel of the nanopore. Through the use of “tags” or modifications to the outside of the nanopores, the researcher can generate a distinct current from the interaction of the tag and the specific molecule. Each tag is specific to the desired molecule, much like a lock and key; this then allows for this specific molecule to be discerned from a mixture of various nonspecific ones.[61] Over the years researchers have realized that RNAs can serve as biomarkers for diseases and even rate of progression.[75][76][77][78][79] This application for RNA Single Pore Sensing through bacteriophages is still nascent and undiscovered territory.[80]
Single pore sensing of polypeptides can be described readily by the amount of current blockage they produce.[61] With the current issue of the nanopore channel size being small, larger polypeptides or proteins are unable to be translocated. Yet the molecules can still be analyzed due to the conformational changes they trigger while interacting with the external portion of the connector. Therefore in chemical detection, dwell time can be related to either the time required for completed translocation or the length of time the molecule interacted with the outside of the nanopore.[81][82][83]
Over the years, the nanopore-based sensing technique has been developed for the detection of various molecules and has proven its potential for the diagnosis of diseases.[61]
References
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|s2cid=ignored (help) - ↑ Niu, Haofu; Zhang, Weili; Wei, Liangwan; Liu, Meng; Liu, Hao; Zhao, Changjian; Zhang, Peng; Liao, Quanfeng; Liu, Ya; Yuan, Qingyue; Wu, Siying (2019). "Rapid Nanopore Assay for Carbapenem-Resistant Klebsiella pneumoniae". Frontiers in Microbiology. 10: 1672. doi:10.3389/fmicb.2019.01672. ISSN 1664-302X. PMC 6682601 Check
|pmc=value (help). PMID 31417504. - ↑ Sun, Ke; Zhao, Changjian; Zeng, Xiaojun; Chen, Yuejia; Jiang, Xin; Ding, Xianting; Gou, Lu; Xie, Haiyang; Li, Xinqiong; Zhang, Xialin; Lin, Sheng (2019-11-08). "Active DNA unwinding and transport by a membrane-adapted helicase nanopore". Nature Communications. 10 (1): 5083. Bibcode:2019NatCo..10.5083S. doi:10.1038/s41467-019-13047-y. ISSN 2041-1723. PMC 6841704 Check
|pmc=value (help). PMID 31704937. - ↑ 48.0 48.1 Haque, Farzin; Geng, Jia; Montemagno, Carlo; Guo, Peixuan (February 2013). "Incorporation of a viral DNA-packaging motor channel in lipid bilayers for real-time, single-molecule sensing of chemicals and double-stranded DNA". Nature Protocols. 8 (2): 373–392. doi:10.1038/nprot.2013.001. ISSN 1750-2799. PMC 3866906. PMID 23348364.
- ↑ 49.0 49.1 Wendell, David; Jing, Peng; Geng, Jia; Subramaniam, Varuni; Lee, Tae Jin; Montemagno, Carlo; Guo, Peixuan (November 2009). "Translocation of double-stranded DNA through membrane-adapted phi29 motor protein nanopores". Nature Nanotechnology. 4 (11): 765–772. Bibcode:2009NatNa...4..765W. doi:10.1038/nnano.2009.259. ISSN 1748-3395. PMC 2777743. PMID 19893523.
- ↑ Varongchayakul, Nitinun; Song, Jiaxi; Meller, Amit; Grinstaff, Mark W. (2018-11-26). "Single-molecule protein sensing in a nanopore: a tutorial". Chemical Society Reviews. 47 (23): 8512–8524. doi:10.1039/C8CS00106E. ISSN 1460-4744. PMC 6309966. PMID 30328860.
- ↑ Deamer, David W.; Branton, Daniel (2002-10-01). "Characterization of Nucleic Acids by Nanopore Analysis". Accounts of Chemical Research. 35 (10): 817–825. doi:10.1021/ar000138m. ISSN 0001-4842. PMID 12379134.
- ↑ Jing, Peng; Haque, Farzin; Shu, Dan; Montemagno, Carlo; Guo, Peixuan (2010-09-08). "One-Way Traffic of a Viral Motor Channel for Double-Stranded DNA Translocation". Nano Letters. 10 (9): 3620–3627. Bibcode:2010NanoL..10.3620J. doi:10.1021/nl101939e. ISSN 1530-6984. PMC 2935672. PMID 20722407.
- ↑ Gu, Zhen; Ying, Yi-Lun; Cao, Chan; He, Pingang; Long, Yi-Tao (2015-01-20). "Accurate Data Process for Nanopore Analysis". Analytical Chemistry. 87 (2): 907–913. doi:10.1021/ac5028758. ISSN 0003-2700. PMID 25514172.
- ↑ Lv, Wenping; Liu, Shengju; Li, Xin; Wu, Ren'an (2014). "Spatial blockage of ionic current for electrophoretic translocation of DNA through a graphene nanopore". Electrophoresis. 35 (8): 1144–1151. arXiv:1302.3671. doi:10.1002/elps.201300501. ISSN 1522-2683. PMID 24459097. Unknown parameter
|s2cid=ignored (help) - ↑ Qiu, Yinghua; Lin, Chih-Yuan; Hinkle, Preston; Plett, Timothy S.; Yang, Crystal; Chacko, Jenu Varghese; Digman, Michelle A.; Yeh, Li-Hsien; Hsu, Jyh-Ping; Siwy, Zuzanna S. (2016-09-27). "Highly Charged Particles Cause a Larger Current Blockage in Micropores Compared to Neutral Particles". ACS Nano. 10 (9): 8413–8422. doi:10.1021/acsnano.6b03280. ISSN 1936-0851. PMID 27532683.
- ↑ Rajeev, Gayathri; Cowin, Allison J.; Voelcker, Nicolas H.; Prieto Simon, Beatriz (2019). "Magnetic Nanoparticles Enhance Pore Blockage-Based Electrochemical Detection of a Wound Biomarker". Frontiers in Chemistry. 7: 438. Bibcode:2019FrCh....7..438P. doi:10.3389/fchem.2019.00438. ISSN 2296-2646. PMC 6582131 Check
|pmc=value (help). PMID 31245362. - ↑ Geng, Jia; Wang, Shaoying; Fang, Huaming; Guo, Peixuan (2013-04-23). "Channel Size Conversion of Phi29 DNA-Packaging Nanomotor for Discrimination of Single- and Double-Stranded Nucleic Acids". ACS Nano. 7 (4): 3315–3323. doi:10.1021/nn400020z. ISSN 1936-0851. PMC 3663147. PMID 23488809.
- ↑ Ji, Zhouxiang; Guo, Peixuan (2019-09-01). "Channel from bacterial virus T7 DNA packaging motor for the differentiation of peptides composed of a mixture of acidic and basic amino acids". Biomaterials. 214: 119222. doi:10.1016/j.biomaterials.2019.119222. ISSN 0142-9612. PMC 6724551 Check
|pmc=value (help). PMID 31158604. - ↑ Meller, Amit; Lucas; Branton, Daniel (2001-04-09). "Voltage-Driven DNA Translocations through a Nanopore". Physical Review Letters. 86 (15): 3435–3438. Bibcode:2001PhRvL..86.3435M. doi:10.1103/PhysRevLett.86.3435. PMID 11327989.
- ↑ 60.0 60.1 60.2 Haque, Farzin; Lunn, Jennifer; Fang, Huaming; Smithrud, David; Guo, Peixuan (2012-04-24). "Real-Time Sensing and Discrimination of Single Chemicals Using the Channel of Phi29 DNA Packaging Nanomotor". ACS Nano. 6 (4): 3251–3261. doi:10.1021/nn3001615. ISSN 1936-0851. PMC 3337346. PMID 22458779.
- ↑ 61.0 61.1 61.2 61.3 Wang, Shaoying; Haque, Farzin; Rychahou, Piotr G.; Evers, B. Mark; Guo, Peixuan (2013-11-26). "Engineered Nanopore of Phi29 DNA-Packaging Motor for Real-Time Detection of Single Colon Cancer Specific Antibody in Serum". ACS Nano. 7 (11): 9814–9822. doi:10.1021/nn404435v. ISSN 1936-0851. PMC 3915501. PMID 24152066.
- ↑ Li, Qiao; Ying, Yi-Lun; Liu, Shao-Chuang; Lin, Yao; Long, Yi-Tao (2019-05-24). "Detection of Single Proteins with a General Nanopore Sensor". ACS Sensors. 4 (5): 1185–1189. doi:10.1021/acssensors.9b00228. PMID 30860364. Unknown parameter
|s2cid=ignored (help) - ↑ Ling, Daniel Y; Ling, Xinsheng Sean (2013-08-21). "On the distribution of DNA translocation times in solid-state nanopores: an analysis using Schrödinger's first-passage-time theory". Journal of Physics: Condensed Matter. 25 (37): 375102. Bibcode:2013JPCM...25K5102Y. doi:10.1088/0953-8984/25/37/375102. ISSN 0953-8984. PMC 4778962. PMID 23963318.
- ↑ Wei, Zi-Xuan; Ying, Yi-Lun; Li, Meng-Yin; Yang, Jie; Zhou, Jia-Le; Wang, Hui-Feng; Yan, Bing-Yong; Long, Yi-Tao (2019-08-06). "Learning Shapelets for Improving Single-Molecule Nanopore Sensing". Analytical Chemistry. 91 (15): 10033–10039. doi:10.1021/acs.analchem.9b01896. ISSN 0003-2700. PMID 31083925. Unknown parameter
|s2cid=ignored (help) - ↑ Tan, Cherie S.; Fleming, Aaron M.; Ren, Hang; Burrows, Cynthia J.; White, Henry S. (2018-10-31). "γ-Hemolysin Nanopore Is Sensitive to Guanine-to-Inosine Substitutions in Double-Stranded DNA at the Single-Molecule Level". Journal of the American Chemical Society. 140 (43): 14224–14234. doi:10.1021/jacs.8b08153. ISSN 0002-7863. PMC 6242276. PMID 30269492.
- ↑ 66.0 66.1 Lin, Kabin; Lin, Chih-Yuan; Polster, Jake W.; Chen, Yunfei; Siwy, Zuzanna S. (2020-02-12). "Charge Inversion and Calcium Gating in Mixtures of Ions in Nanopores". Journal of the American Chemical Society. 142 (6): 2925–2934. doi:10.1021/jacs.9b11537. ISSN 0002-7863. PMID 31964139. Unknown parameter
|s2cid=ignored (help) - ↑ 67.0 67.1 Sheng, Yingying; Zhang, Shouwen; Liu, Lei; Wu, Hai-Chen (2020). "Measuring Enzymatic Activities with Nanopores". ChemBioChem. 21 (15): 2089–2097. doi:10.1002/cbic.202000079. ISSN 1439-7633. PMID 32202055 Check
|pmid=value (help). Unknown parameter|s2cid=ignored (help) - ↑ 68.0 68.1 Si, Wei; Sha, Jingjie; Sun, Qianyi; He, Zhen; Wu, Liang; Chen, Chang; Yu, Shuhong; Chen, Yunfei (2020-03-02). "Shape characterization and discrimination of single nanoparticles using solid-state nanopores". Analyst. 145 (5): 1657–1666. Bibcode:2020Ana...145.1657S. doi:10.1039/C9AN01889A. ISSN 1364-5528. PMID 31922169. Unknown parameter
|s2cid=ignored (help) - ↑ 69.0 69.1 Zhao, Yating; Liu, Lei; Tu, Yingfeng; Wu, Hai-Chen (2019). "Investigating the effect of mono- and multivalent counterions on the conformation of poly(styrenesulfonic acid) by nanopores". Electrophoresis. 40 (16–17): 2180–2185. doi:10.1002/elps.201800539. ISSN 1522-2683. PMID 30811621. Unknown parameter
|s2cid=ignored (help) - ↑ Geng, Jia; Wang, Shaoying; Fang, Huaming; Guo, Peixuan (2013-04-23). "Channel Size Conversion of Phi29 DNA-Packaging Nanomotor for Discrimination of Single- and Double-Stranded Nucleic Acids". ACS Nano. 7 (4): 3315–3323. doi:10.1021/nn400020z. ISSN 1936-0851. PMC 3663147. PMID 23488809.
- ↑ McIntyre, Alexa B. R.; Alexander, Noah; Grigorev, Kirill; Bezdan, Daniela; Sichtig, Heike; Chiu, Charles Y.; Mason, Christopher E. (2019-02-04). "Single-molecule sequencing detection of N 6-methyladenine in microbial reference materials". Nature Communications. 10 (1): 579. Bibcode:2019NatCo..10..579M. doi:10.1038/s41467-019-08289-9. ISSN 2041-1723. PMC 6362088. PMID 30718479.
- ↑ Ji, Zhouxiang; Kang, Xinqi; Wang, Shaoying; Guo, Peixuan (2018-11-01). "Nano-channel of viral DNA packaging motor as single pore to differentiate peptides with single amino acid difference". Biomaterials. 182: 227–233. doi:10.1016/j.biomaterials.2018.08.005. ISSN 0142-9612. PMC 6309972. PMID 30138785.
- ↑ Wang, Shaoying; Zhao, Zhengyi; Haque, Farzin; Guo, Peixuan (2018-06-01). "Engineering of protein nanopores for sequencing, chemical or protein sensing and disease diagnosis". Current Opinion in Biotechnology. 51: 80–89. doi:10.1016/j.copbio.2017.11.006. ISSN 0958-1669. PMC 5994363. PMID 29232619.
- ↑ Kono, Nobuaki; Arakawa, Kazuharu (2019). "Nanopore sequencing: Review of potential applications in functional genomics". Development, Growth & Differentiation. 61 (5): 316–326. doi:10.1111/dgd.12608. ISSN 1440-169X. PMID 31037722. Unknown parameter
|s2cid=ignored (help) - ↑ Arantes, Lidia Maria Rebolho Batista; Carvalho, Ana Carolina De; Melendez, Matias Eliseo; Carvalho, André Lopes (2018-01-02). "Serum, plasma and saliva biomarkers for head and neck cancer". Expert Review of Molecular Diagnostics. 18 (1): 85–112. doi:10.1080/14737159.2017.1404906. ISSN 1473-7159. PMID 29134827. Unknown parameter
|s2cid=ignored (help) - ↑ Meng, Shujuan; Zhou, Hecheng; Feng, Ziyang; Xu, Zihao; Tang, Ying; Li, Peiyao; Wu, Minghua (2017-05-23). "CircRNA: functions and properties of a novel potential biomarker for cancer". Molecular Cancer. 16 (1): 94. doi:10.1186/s12943-017-0663-2. ISSN 1476-4598. PMC 5440908. PMID 28535767.
- ↑ Rysz, Jacek; Gluba-Brzózka, Anna; Franczyk, Beata; Jabłonowski, Zbigniew; Ciałkowska-Rysz, Aleksandra (August 2017). "Novel Biomarkers in the Diagnosis of Chronic Kidney Disease and the Prediction of Its Outcome". International Journal of Molecular Sciences. 18 (8): 1702. doi:10.3390/ijms18081702. PMC 5578092. PMID 28777303.
- ↑ Yang, Guodong; Lu, Xiaozhao; Yuan, Lijun (2014-11-01). "LncRNA: A link between RNA and cancer". Biochimica et Biophysica Acta (BBA) - Gene Regulatory Mechanisms. 1839 (11): 1097–1109. doi:10.1016/j.bbagrm.2014.08.012. ISSN 1874-9399. PMID 25159663.
- ↑ Zhu, Lei; Li, Jiao; Gong, Youling; Wu, Qingbin; Tan, Shuangyan; Sun, Dan; Xu, Xiaomin; Zuo, Yuanli; Zhao, Yun; Wei, Yu-Quan; Wei, Xia-Wei (2019-04-02). "Exosomal tRNA-derived small RNA as a promising biomarker for cancer diagnosis". Molecular Cancer. 18 (1): 74. doi:10.1186/s12943-019-1000-8. ISSN 1476-4598. PMC 6444574. PMID 30940133.
- ↑ Yang, Jie; Wang, Ya-Qian; Li, Meng-Yin; Ying, Yi-Lun; Long, Yi-Tao (2018-12-11). "Direct Sensing of Single Native RNA with a Single-Biomolecule Interface of Aerolysin Nanopore". Langmuir. 34 (49): 14940–14945. doi:10.1021/acs.langmuir.8b03264. ISSN 0743-7463. PMID 30462509. Unknown parameter
|s2cid=ignored (help) - ↑ Ouldali, Hadjer; Sarthak, Kumar; Ensslen, Tobias; Piguet, Fabien; Manivet, Philippe; Pelta, Juan; Behrends, Jan C.; Aksimentiev, Aleksei; Oukhaled, Abdelghani (February 2020). "Electrical recognition of the twenty proteinogenic amino acids using an aerolysin nanopore". Nature Biotechnology. 38 (2): 176–181. doi:10.1038/s41587-019-0345-2. ISSN 1546-1696. PMC 7008938 Check
|pmc=value (help). PMID 31844293. - ↑ Piguet, Fabien; Ouldali, Hadjer; Pastoriza-Gallego, Manuela; Manivet, Philippe; Pelta, Juan; Oukhaled, Abdelghani (2018-03-06). "Identification of single amino acid differences in uniformly charged homopolymeric peptides with aerolysin nanopore". Nature Communications. 9 (1): 966. Bibcode:2018NatCo...9..966P. doi:10.1038/s41467-018-03418-2. ISSN 2041-1723. PMC 5840376. PMID 29511176.
- ↑ Restrepo-Pérez, Laura; Huang, Gang; Bohländer, Peggy R.; Worp, Nathalie; Eelkema, Rienk; Maglia, Giovanni; Joo, Chirlmin; Dekker, Cees (2019-12-24). "Resolving Chemical Modifications to a Single Amino Acid within a Peptide Using a Biological Nanopore". ACS Nano. 13 (12): 13668–13676. doi:10.1021/acsnano.9b05156. ISSN 1936-0851. PMC 6933820 Check
|pmc=value (help). PMID 31536327.
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