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Narrowing Signal Distribution by Adamantane Derivatization for Amino Acid Identification Using α-Hemolysin Nanopore



Xiaojun Wei, Dumei Ma, Junlin Ou, Ge Song, Jiawei Guo, Joseph Robertson, Yi Wang, Qian Wang, Chang Liu


Nanopores have demonstrated remarkable sensitivity as biosensors, enabling the sequencing of DNA and RNA at the single-molecule level. The rapid progress in this field has sparked interest in using nanopores for protein sequencing, although current attempts are hindered by the challenge of accurately identifying amino acids, especially in regard to distinguishing between those that are very similar. Innovative solutions are needed to overcome current limitations. One approach is to label amino acids with functional groups that help generate distinct nanopore ionic current signals. However, a high degree of chemical specificity is required to avoid downstream misidentification of amino acids. In this study, we employed adamantane as a novel modification structure to label proteinogenic amino acids and developed an approach to fingerprint individual amino acids using the α-hemolysin nanopore. The rigid and closed-loop structure of adamantane improved the spatial resolution of adamantane-labeled amino acids (ALAAs), resulting in distinctive nanopore current signals. The spatial conformations of these ALAAs were investigated and the utility of various nanopore parameters for amino acid discrimination was explored, using molecular modeling. Our strategy successfully distinguished nine selected proteinogenic amino acids. To automate event classification, a custom machine-learning algorithm was developed, which delivered an 81.3% validation accuracy. Our results not only represent a significant step forward in the development of a single-molecule protein-fingerprinting approach using nanopores, but also offer a potential platform for exploring intrinsic and variant structures of molecules at the single-molecule level.
Nano Letters


protein sequencing, nanopore


Wei, X. , Ma, D. , Ou, J. , Song, G. , Guo, J. , Robertson, J. , Wang, Y. , Wang, Q. and Liu, C. (2024), Narrowing Signal Distribution by Adamantane Derivatization for Amino Acid Identification Using α-Hemolysin Nanopore, Nano Letters, [online],, (Accessed July 13, 2024)


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Created January 24, 2024, Updated January 29, 2024