Abstract
The chemical functionalities within biopolymers determine their physical properties and biological activities. The relationship between the side chains available to a biopolymer population and the potential functions of the resulting polymers, however, has proven difficult to study experimentally. Using seven sets of chemically diverse charged, polar, and nonpolar side chains, we performed cycles of artificial translation, in vitro selections for binding to either PCSK9 or IL-6 protein, and replication on libraries of random side chain-functionalized nucleic acid polymers. Polymer sequence convergence, bulk population target binding, affinity of individual polymers, and head-to-head competition among post-selection libraries collectively indicate that polymer libraries with nonpolar side chains outperformed libraries lacking these side chains. The presence of nonpolar groups, resembling functionality existing in proteins but missing from natural nucleic acids, thus may be strong determinants of binding activity. This factor may contribute to the apparent evolutionary advantage of proteins over their nucleic acid precursors for some molecular recognition tasks.
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High-throughput sequencing data will be available from the NCBI Sequence Read Archive under accession code SRP153119.
Change history
11 March 2019
In the version of this article originally published, several data points in Fig. 4c were shifted out of place during production. The corrected version of Fig. 4c is shown below. This error has been corrected in the PDF and HTML versions of the article.
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Acknowledgements
This work was supported by DARPA N66001-14-2-4053, NIH R35 GM118062, and the Howard Hughes Medical Institute. Z.C. was partially supported by the Y. Kishi Graduate Prize in Chemistry and Chemical Biology sponsored by the Eisai Corporation. The authors thank A. Chan, J.P. Maianti, M. Packer, D.L. Usanov, B. Thuronyi, and C. Wilson for helpful comments and discussions. We also thank K. Arnett and R. Stoller for guidance with SPR experiments and analysis.
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P.A.L., Z.C., J.C.C. performed experiments; P.A.L. and N.H.E. developed the SPR methodology; P.A.L., Z.C., and D.R.L. designed the research and wrote the manuscript; all authors reviewed and edited the manuscript.
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Z.C., P.A.L., and D.R.L. have filed patent applications on DNA-templated polymerization.
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Lichtor, P.A., Chen, Z., Elowe, N.H. et al. Side chain determinants of biopolymer function during selection and replication. Nat Chem Biol 15, 419–426 (2019). https://doi.org/10.1038/s41589-019-0229-2
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DOI: https://doi.org/10.1038/s41589-019-0229-2
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