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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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.
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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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). https://doi.org/10.1038/s41565-019-0579-7
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