4.8 Article

De novo 3D models of SARS-CoV-2 RNA elements from consensus experimental secondary structures

Journal

NUCLEIC ACIDS RESEARCH
Volume 49, Issue 6, Pages 3092-3108

Publisher

OXFORD UNIV PRESS
DOI: 10.1093/nar/gkab119

Keywords

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Funding

  1. National Science Foundation Graduate Research Fellowship Program [DGE-1656518]
  2. Stanford Graduate Fellowship
  3. Stanford Summer Research Program (SSRP)
  4. CSUN BUILD PODER
  5. Stanford ChEM-HCOVID-19 Drug and Vaccine Prototyping seed grant
  6. National Institutes of Health [R21 AI145647, R35 GM122579]
  7. National Science Foundation [2030508]

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This study provides 3D models of SARS-CoV-2 RNA regions based on chemical mapping data and Rosetta's algorithm to develop small molecule antivirals. Modeling convergence supports high accuracy of predicted low energy states, with subsequent experimental validation. Additionally, models of RNA riboswitches are provided, offering new directions for discovering RNA binders.
The rapid spread of COVID-19 is motivating development of antivirals targeting conserved SARS-CoV-2 molecular machinery. The SARS-CoV-2 genome includes conserved RNA elements that offer potential small-molecule drug targets, but most of their 3D structures have not been experimentally characterized. Here, we provide a compilation of chemical mapping data from our and other labs, secondary structure models, and 3D model ensembles based on Rosetta's FARFAR2 algorithm for SARS-CoV-2 RNA regions including the individual stems SL1-8 in the extended 5' UTR; the reverse complement of the 5' UTR SL1-4; the frameshift stimulating element (FSE); and the extended pseudoknot, hypervariable region, and s2m of the 3' UTR. For eleven of these elements (the stems in SL1-8, reverse complement of SL1-4, FSE, s2m and 3' UTR pseudoknot), modeling convergence supports the accuracy of predicted low energy states; subsequent cryo-EM characterization of the FSE confirms modeling accuracy. To aid efforts to discover small molecule RNA binders guided by computational models, we provide a second set of similarly prepared models for RNA riboswitches that bind small molecules. Both datasets ('FARFAR2-SARS-CoV-2', https://github.com/DasLab/FARFAR2-SARS-CoV-2; and 'FARFAR2-Apo-Riboswitch', at https://github.com/DasLab/FARFAR2-Apo-Riboswitch') include up to 400 models for each RNA element, which may facilitate drug discovery approaches targeting dynamic ensembles of RNA molecules.

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