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ABSTRACT The physicochemical properties of nucleic acids are dominated by their highly charged phosphodiester backbone chemistry. This polyelectrolyte structure decouples information content

(base sequence) from bulk properties, such as solubility, and has been proposed as a defining trait of all informational polymers. However, this conjecture has not been tested

experimentally. Here, we describe the encoded synthesis of a genetic polymer with an uncharged backbone chemistry: alkyl phosphonate nucleic acids (phNAs) in which the canonical, negatively

charged phosphodiester is replaced by an uncharged P-alkyl phosphonodiester backbone. Using synthetic chemistry and polymerase engineering, we describe the enzymatic, DNA-templated synthesis

of P-methyl and P-ethyl phNAs, and the directed evolution of specific streptavidin-binding phNA aptamer ligands directly from random-sequence mixed P-methyl/P-ethyl phNA repertoires. Our

results establish an example of the DNA-templated enzymatic synthesis and evolution of an uncharged genetic polymer and provide a foundational methodology for their exploration as a source

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SIMILAR CONTENT BEING VIEWED BY OTHERS A MATING MECHANISM TO GENERATE DIVERSITY FOR THE DARWINIAN SELECTION OF DNA-ENCODED SYNTHETIC MOLECULES Article 06 December 2021 SYNTHETIC DNA

APPLICATIONS IN INFORMATION TECHNOLOGY Article Open access 17 January 2022 DIRECTED EVOLUTION AND SELECTION OF BIOSTABLE L-DNA APTAMERS WITH A MIRROR-IMAGE DNA POLYMERASE Article Open access

06 June 2022 DATA AVAILABILITY The authors declare that the data supporting the findings of this study are available within the article and its Supplementary Information files. The

molecular modelling data and related settings for computations that support the findings of this study are available in the Zenodo database (https://zenodo.org/) with the following record

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(S.A.,-F.), by the Medical Research Council (S.A.-F. A.I.T., S.P.-C., P.H., program no. MC_U105178804), by the Biotechnology and Biological Sciences Research Council (B.T.P., BBSRC grant no

BB/N01023x/1), by the NICHD/ NIH Intramural Research Program (A.V. and R.W.) and by a European Molecular Biology Organization (EMBO) Long-Term Fellowship (V.G., ALTF 103-2018). AUTHOR

INFORMATION AUTHORS AND AFFILIATIONS * MRC Laboratory of Molecular Biology, Francis Crick Avenue, Cambridge Biomedical Campus, Cambridge, UK Sebastian Arangundy-Franklin, Alexander I.

Taylor, Benjamin T. Porebski, Sew Peak-Chew & Philipp Holliger * Institute for Research in Biomedicine (IRB Barcelona), The Barcelona Institute of Science and Technology, Barcelona,

Spain Vito Genna & Modesto Orozco * Section on DNA Replication, Repair and Mutagenesis, Bethesda, MD, USA Alexandra Vaisman & Roger Woodgate * Department of Biochemistry and

Biomedicine, University of Barcelona, Barcelona, Spain Modesto Orozco Authors * Sebastian Arangundy-Franklin View author publications You can also search for this author inPubMed Google

Scholar * Alexander I. Taylor View author publications You can also search for this author inPubMed Google Scholar * Benjamin T. Porebski View author publications You can also search for

this author inPubMed Google Scholar * Vito Genna View author publications You can also search for this author inPubMed Google Scholar * Sew Peak-Chew View author publications You can also

search for this author inPubMed Google Scholar * Alexandra Vaisman View author publications You can also search for this author inPubMed Google Scholar * Roger Woodgate View author

publications You can also search for this author inPubMed Google Scholar * Modesto Orozco View author publications You can also search for this author inPubMed Google Scholar * Philipp

Holliger View author publications You can also search for this author inPubMed Google Scholar CONTRIBUTIONS S.A.-F. and P.H. conceived and designed the experiments. S.A.-F. performed all the

experiments except the SPR measurements (A.T. and B.T.P.), MS (S.P.-C.) and steady-state kinetics (A.V. and R.W.) and Modelling and MD simulations (V.G. and M.O.). All the authors discussed

the results, and jointly wrote the manuscript. CORRESPONDING AUTHOR Correspondence to Philipp Holliger. ETHICS DECLARATIONS CONFLICT OF INTEREST The authors declare no competing interests.

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CITE THIS ARTICLE Arangundy-Franklin, S., Taylor, A.I., Porebski, B.T. _et al._ A synthetic genetic polymer with an uncharged backbone chemistry based on alkyl phosphonate nucleic acids.

_Nat. Chem._ 11, 533–542 (2019). https://doi.org/10.1038/s41557-019-0255-4 Download citation * Received: 09 March 2018 * Accepted: 15 March 2019 * Published: 22 April 2019 * Issue Date: June

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