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An autonomous molecular assembler for programmable chemical synthesis

Abstract

Molecular machines that assemble polymers in a programmed sequence are fundamental to life. They are also an achievable goal of nanotechnology. Here, we report synthetic molecular machinery made from DNA that controls and records the formation of covalent bonds. We show that an autonomous cascade of DNA hybridization reactions can create oligomers, from building blocks linked by olefin or peptide bonds, with a sequence defined by a reconfigurable molecular program. The system can also be programmed to achieve combinatorial assembly. The sequence of assembly reactions and thus the structure of each oligomer synthesized is recorded in a DNA molecule, which enables this information to be recovered by PCR amplification followed by DNA sequencing.

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Figure 1: Operation of the assembler.
Figure 2: Ordered synthesis of a diolefin product.
Figure 3: Programmed synthesis of a polypeptide with a single, repeated building block.
Figure 4: Programmed combinatorial synthesis of a polypeptide.
Figure 5: Recording the reaction sequence.

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Acknowledgements

The authors thank E. Stulz and L. Gong for discussions. This research was supported by Biotechnology and Biological Sciences Research Council sLOLA grants BB/J00054X/1 and BB/J001694/2, Engineering and Physical Sciences Research Council grants EP/F056605/1, EP/F008597/1, EP/I016651/1, EP/F055803/1, EP/F009062/1, EP/G037930/1 and EP/P504287/1, and a Royal Society–Wolfson Research Merit Award (to A.J.T.).

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W.M., R.A.M., M.L.M. and P.J.M. performed the experiments. W.M., R.A.M., M.L.M., P.J.M., J.B., R.K.O'R. and A.J.T. contributed to experimental design, interpretation of data and preparation of the manuscript. A.E.S., T.B. and B.G.D. provided critical materials and advice on covalent reactions and product purification.

Corresponding author

Correspondence to Andrew J. Turberfield.

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The authors declare no competing financial interests.

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Meng, W., Muscat, R., McKee, M. et al. An autonomous molecular assembler for programmable chemical synthesis. Nature Chem 8, 542–548 (2016). https://doi.org/10.1038/nchem.2495

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