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Blind prediction of noncanonical RNA structure at atomic accuracy

View ORCID ProfileAndrew Watkins, Caleb Geniesse, Wipapat Kladwang, Paul Zakrevsky, Luc Jaeger, View ORCID ProfileRhiju Das
doi: https://doi.org/10.1101/223305
Andrew Watkins
1Department of Biochemistry, Stanford University School of Medicine, Stanford, CA 94305.
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Caleb Geniesse
1Department of Biochemistry, Stanford University School of Medicine, Stanford, CA 94305.
2Biophysics Program, Stanford University, Stanford, CA 94305.
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Wipapat Kladwang
1Department of Biochemistry, Stanford University School of Medicine, Stanford, CA 94305.
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Paul Zakrevsky
3Department of Chemistry, University of California, Santa Barbara, Santa Barbara, CA 93106.
4Current affiliation: RNA Biology Laboratory, Center for Cancer Research, National Cancer Institute, Frederick, MD 21702
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Luc Jaeger
4Current affiliation: RNA Biology Laboratory, Center for Cancer Research, National Cancer Institute, Frederick, MD 21702
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Rhiju Das
1Department of Biochemistry, Stanford University School of Medicine, Stanford, CA 94305.
2Biophysics Program, Stanford University, Stanford, CA 94305.
5Department of Physics, Stanford University, Stanford, CA 94305.
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  • For correspondence: rhiju@stanford.edu
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Abstract

Prediction of RNA structure from nucleotide sequence remains an unsolved grand challenge of biochemistry and requires distinct concepts from protein structure prediction. Despite extensive algorithmic development in recent years, modeling of noncanonical base pairs of new RNA structural motifs has not been achieved in blind challenges. We report herein a stepwise Monte Carlo (SWM) method with a unique add-and-delete move set that enables predictions of noncanonical base pairs of complex RNA structures. A benchmark of 82 diverse motifs establishes the method’s general ability to recover noncanonical pairs ab initio, including multistrand motifs that have been refractory to prior approaches. In a blind challenge, SWM models predicted nucleotide-resolution chemical mapping and compensatory mutagenesis experiments for three in vitro selected tetraloop/receptors with previously unsolved structures (C7.2, C7.10, and R1). As a final test, SWM blindly and correctly predicted all noncanonical pairs of a Zika virus double pseudoknot during a recent community-wide RNA-puzzle. Stepwise structure formation, as encoded in the SWM method, enables modeling of noncanonical RNA structure in a variety of previously intractable problems.

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Posted February 06, 2018.
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Blind prediction of noncanonical RNA structure at atomic accuracy
Andrew Watkins, Caleb Geniesse, Wipapat Kladwang, Paul Zakrevsky, Luc Jaeger, Rhiju Das
bioRxiv 223305; doi: https://doi.org/10.1101/223305
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Blind prediction of noncanonical RNA structure at atomic accuracy
Andrew Watkins, Caleb Geniesse, Wipapat Kladwang, Paul Zakrevsky, Luc Jaeger, Rhiju Das
bioRxiv 223305; doi: https://doi.org/10.1101/223305

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