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Catalytic site-selective substrate processing within a tubular nanoreactor


Chemists have long sought the ability to modify molecules precisely when presented with several sites of similar reactivity. We reasoned that the confinement of substrates within nanostructures might permit site-selective reactions unachievable in bulk solution, even with sophisticated reagents. In particular, the stretching and alignment of polymers within nanotubes might allow site-specific cleavage or modification. To explore this proposition, macromolecular disulfide substrates were elongated within members of a collection of tubular protein nanoreactors, which contained cysteine residues positioned at different locations along the length of each tube. For each nanoreactor, we defined the reactive location by using a set of polymer substrates (site-selectivity) and which of the two sulfur atoms was attacked (regioselectivity), and found that disulfide interchange occurs with atomic precision. Our strategy has potential for the selective processing of a wide variety of biomacromolecules, and the chemistry and substrates might be generalized yet further by using alternative nanotubes.

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Fig. 1: Substrate processing within a protein nanotube.
Fig. 2: Nanoscale alignment of a substrate disulfide with a nanoreactor cysteine sulfur determines reactivity.
Fig. 3: Regioselectivity of single-molecule thiol–disulfide interchange.
Fig. 4: Tandem thiol–disulfide interchanges with double-cysteine nanoreactors.

Data availability

The data that support the plots within this paper and other findings of this study are available from the corresponding author upon reasonable request.


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We thank L. Taemaitree for her help with LC–MS characterization. We also thank M. Booth for useful discussions and M. Howarth for providing a sample of traptavidin for preliminary tests. This research was supported by a European Research Council Advanced Grant (COSIMO). Y.Q. was supported by a China Scholarship Council-University of Oxford Scholarship. S.A.I. was funded by an Amelia Jackson Studentship, Exeter College, Oxford.

Author information




Y.Q. and H.B. conceived the research. Y.Q. performed the experiments. H.T.-A. contributed to the solid-phase peptide synthesis. S.A.I. and M.D.L. contributed to the electrical measurements. Y.Q., S.A.I. and H.B. wrote the manuscript. All authors discussed the results and commented on the manuscript.

Corresponding author

Correspondence to Hagan Bayley.

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Competing interests

Y.Q. and H.B. have filed patents describing the molecular hopper and applications thereof. The hopper is ratcheted by regioselective thiol–disulfide interchange.

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Supplementary information

Supplementary Information

Supplementary notes, Table 1 and 2, Figs. 1–9 and refs. 1–10.

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Qing, Y., Tamagaki-Asahina, H., Ionescu, S.A. et al. Catalytic site-selective substrate processing within a tubular nanoreactor. Nat. Nanotechnol. 14, 1135–1142 (2019).

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