1. De novo3D models of SARS-CoV-2 RNA elements from consensus experimental secondary structures
- Author
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Andrew M. Watkins, Gregory Thain, Ivan N Zheludev, Mats Rynge, Jose Chacon, Rhiju Das, Wipapat Kladwang, Jill Townley, Ramya Rangan, and Rachael Kretsch
- Subjects
Models, Molecular ,Untranslated region ,Riboswitch ,RNA Stability ,Consensus ,AcademicSubjects/SCI00010 ,Drug Evaluation, Preclinical ,Datasets as Topic ,Genome, Viral ,Computational biology ,Complementarity determining region ,Biology ,010402 general chemistry ,01 natural sciences ,Genome ,Small Molecule Libraries ,03 medical and health sciences ,Genetics ,3' Untranslated Regions ,030304 developmental biology ,0303 health sciences ,Binding Sites ,Base Sequence ,SARS-CoV-2 ,Drug discovery ,Cryoelectron Microscopy ,Computational Biology ,Frameshifting, Ribosomal ,Reproducibility of Results ,RNA ,Aptamers, Nucleotide ,0104 chemical sciences ,Nucleic Acid Conformation ,RNA, Viral ,5' Untranslated Regions ,Pseudoknot ,Algorithms - Abstract
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., Graphical Abstract Graphical Abstract De novo 3D models of SARS-CoV-2 RNA elements and small-molecule-binding RNAs to aid drug discovery.
- Published
- 2021
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