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Sequence-dependent RNA helix conformational preferences predictably impact tertiary structure formation

Yesselman, Joseph D. ; Denny, Sarah K. ; Bisaria, Namita ; Herschlag, Daniel ; Greenleaf, William J. ; Das, Rhiju

Proceedings of the National Academy of Sciences - PNAS, 2019-08, Vol.116 (34), p.16847-16855 [Periódico revisado por pares]

United States: National Academy of Sciences

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  • Título:
    Sequence-dependent RNA helix conformational preferences predictably impact tertiary structure formation
  • Autor: Yesselman, Joseph D. ; Denny, Sarah K. ; Bisaria, Namita ; Herschlag, Daniel ; Greenleaf, William J. ; Das, Rhiju
  • Assuntos: Base Pairing ; Base pairs ; Base Sequence ; Biological activity ; Biological Sciences ; Computer applications ; Gene expression ; Model accuracy ; Models, Molecular ; Nucleic Acid Conformation ; Nucleotide sequence ; Nucleotides ; PNAS Plus ; Protein structure ; Proteins ; Ribonucleic acid ; RNA ; RNA - chemistry ; RNA - genetics ; RNA Stability ; Structural stability ; Tertiary structure ; Thermodynamics ; Variations
  • É parte de: Proceedings of the National Academy of Sciences - PNAS, 2019-08, Vol.116 (34), p.16847-16855
  • Notas: ObjectType-Article-1
    SourceType-Scholarly Journals-1
    ObjectType-Feature-2
    content type line 23
    Author contributions: J.D.Y., S.K.D., D.H., W.J.G., and R.D. designed research; J.D.Y., S.K.D., and N.B. performed research; J.D.Y. and S.K.D. analyzed data, and J.D.Y., S.K.D., and R.D. wrote the paper, with participation by all authors.
    1J.D.Y. and S.K.D. contributed equally to this work.
    3Present address: Whitehead Institute for Biomedical Research, Cambridge, MA 02142.
    Edited by Hashim M. Al-Hashimi, Duke University Medical Center, Durham, NC, and accepted by Editorial Board Member Michael F. Summers June 25, 2019 (received for review February 1, 2019)
    2Present address: Scribe Therapeutics, Berkeley, CA 94704.
  • Descrição: Structured RNAs and RNA complexes underlie biological processes ranging from control of gene expression to protein translation. Approximately 50% of nucleotides within known structured RNAs are folded into Watson–Crick (WC) base pairs, and sequence changes that preserve these pairs are typically assumed to preserve higher-order RNA structure and binding of macromolecule partners. Here, we report that indirect effects of the helix sequence on RNA tertiary stability are, in fact, significant but are nevertheless predictable from a simple computational model called RNAMake-ΔΔG. When tested through the RNA on a massively parallel array (RNA-MaP) experimental platform, blind predictions for >1500 variants of the tectoRNA heterodimer model system achieve high accuracy (rmsd 0.34 and 0.77 kcal/mol for sequence and length changes, respectively). Detailed comparison of predictions to experiments support a microscopic picture of how helix sequence changes subtly modulate conformational fluctuations at each base-pair step, which accumulate to impact RNA tertiary structure stability. Our study reveals a previously overlooked phenomenon in RNA structure formation and provides a framework of computation and experiment for understanding helix conformational preferences and their impact across biological RNA and RNA-protein assemblies.
  • Editor: United States: National Academy of Sciences
  • Idioma: Inglês
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  • Realização: ABCD-USP USP   Logos de Redes Sociais: Freepik

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