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Replication of synthetic recognition-encoded oligomers by ligation of trimer building blocks.

Accepted version
Peer-reviewed

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Authors

Núñez-Villanueva, Diego  ORCID logo  https://orcid.org/0000-0002-1005-1464
Hunter, Christopher A  ORCID logo  https://orcid.org/0000-0002-5182-1859

Abstract

The development of methods for replication of synthetic information oligomers will underpin the use of directed evolution to search new chemical space. Template-directed replication of triazole oligomers has been achieved using a covalent primer in conjunction with non-covalent binding of complementary building blocks. A phenol primer equipped with an alkyne was first attached to a benzoic recognition unit on a mixed sequence template via selective covalent ester base-pair formation. The remaining phenol recognition units on the template were then used for non-covalent binding of phosphine oxide oligomers equipped with an azide. The efficiency of the templated CuAAC reaction between the primer and phosphine oxide building blocks was investigated as a function of the number of H-bonds formed with the template. Increasing the strength of the non-covalent interaction between the template and the azide lead to a significant acceleration of the templated reaction. For shorter phosphine oxide oligomers intermolecular reactions compete with the templated process, but quantitative templated primer elongation was achieved with a phosphine oxide 3-mer building block that was able to form three H-bonds with the template. NMR spectroscopy and molecular models suggest that the template can fold, but addition of the phosphine oxide 3-mer leads to a complex with three H-bonds between phosphine oxide and phenol groups, aligning the azide and alkyne groups in a favourable geometry for the CuAAC reaction. In the product duplex, 1H and 31P NMR data confirm the presence of the three H-bonded base-pairs, demonstrating that the covalent and non-covalent base-pairs are geometrically compatible. A complete replication cycle was carried out starting from the oligotriazole template by covalent attachment of the primer, followed by template-directed elongation, and hydrolysis of the the ester base-pair in the resulting duplex to regenerate the template and liberate the copy strand. We have previously demonstrated sequence-selective oligomer replication using covalent base-pairing, but the trimer building block approach described here is suitable for replication of sequence information using non-covalent binding of the monomer building blocks to a template.

Description

Keywords

3402 Inorganic Chemistry, 3405 Organic Chemistry, 34 Chemical Sciences

Journal Title

Org Chem Front

Conference Name

Journal ISSN

2052-4110
2052-4129

Volume Title

Publisher

Royal Society of Chemistry
Sponsorship
European Commission Horizon 2020 (H2020) ERC (101018984)
European Research Council (320539)
Engineering and Physical Sciences Research Council (EP/P027067/1)
Engineering and Physical Sciences Research Council (EP/P027067/1), the European Research Council (ERC-2020-AdG-101018984-InfoMols) and the Herchel Smith Fund, Fundación General CSIC ́s ComFuturo programme which has received funding from the European Union's Horizon 2020 research and innovation programme under the Marie Skłodowska-Curie grant agreement No. 101034263.