Abstract
Chemical reactions of single molecules, caused by rapid formation or breaking of chemical bonds, are difficult to observe even with state-of-the-art instruments. A biological nanopore can be engineered into a single molecule reactor, capable of detecting the binding of a monatomic ion or the transient appearance of chemical intermediates. Pore engineering of this type is however technically challenging, which has significantly restricted further development of this technique. We propose a versatile strategy, “programmable nano-reactors for stochastic sensing” (PNRSS), by which a variety of single molecule reactions of hydrogen peroxide, metal ions, ethylene glycol, glycerol, lactic acid, vitamins, catecholamines or nucleoside analogues can be observed directly. PNRSS presents a refined sensing resolution which can be further enhanced by an artificial intelligence algorithm. Remdesivir, a nucleoside analogue and an investigational anti-viral drug used to treat COVID-19, can be distinguished from its active triphosphate form by PNRSS, suggesting applications in pharmacokinetics or drug screening.
Highlights
Chemical reactions of single molecules, caused by rapid formation or breaking of chemical bonds, are difficult to observe even with state-of-the-art instruments
Biological nanopores, including α-haemolysin (α-HL)[6], Mycobacterium smegmatis porin A (MspA)[7], aerolysine[8], CsgG9, cytolysin A (ClyA)[10], fragaceatoxin C (FraC)[11], pleurotolysin (PlyA/B)[12], outer membrane protein G13, phi[29] connector[14] and a few others, are a category of large channel proteins developed for single-molecule sensing
The length of the extension section of a programmable nanoreactors for stochastic sensing” (PNRSS) strand is optimized with a 3.5 Å precision so that the reaction section is located at the pore restriction for optimum performance
Summary
Chemical reactions of single molecules, caused by rapid formation or breaking of chemical bonds, are difficult to observe even with state-of-the-art instruments. These events were not observed from another PNRSS strand 14X (Supplementary Fig. 2), confirming that they originate from binding to the dual guanine ligand[43]. Different PNRSS strands such as 14A, with a sole adenine as the fixed reactant, or 14G, with guanine (Supplementary Table 1), have provided events of Ni2+ binding
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