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An RNA dynamic ensemble at atomic resolution

Honglue Shi, Atul Rangadurai, Hala Abou Assi, Rohit Roy, David A. Case, Daniel Herschlag, Joseph D. Yesselman, Hashim M. Al-Hashimi
doi: https://doi.org/10.1101/2020.05.13.092981
Honglue Shi
1Department of Chemistry, Duke University, Durham NC 27710 USA
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Atul Rangadurai
2Department of Biochemistry, Duke University School of Medicine, Durham NC 27710 USA
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Hala Abou Assi
2Department of Biochemistry, Duke University School of Medicine, Durham NC 27710 USA
3Department of Medicine, Duke University School of Medicine, Durham NC 27710 USA
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Rohit Roy
4Center for Genomics and Computational Biology, Duke University School of Medicine, Durham NC 27710 USA
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David A. Case
5Department of Chemistry and Chemical Biology, Rutgers University, Piscataway NJ 08854 USA
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  • For correspondence: hashim.al.hashimi@duke.edu jyesselm@unl.edu herschla@stanford.edu david.case@rutgers.edu
Daniel Herschlag
6Department of Biochemistry, Stanford University, Stanford CA 94305 USA
7Department of Chemical Engineering, Stanford University, Stanford CA 94305 USA
8ChEM-H Institute, Stanford University, Stanford, CA 94305 USA
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  • For correspondence: hashim.al.hashimi@duke.edu jyesselm@unl.edu herschla@stanford.edu david.case@rutgers.edu
Joseph D. Yesselman
9Department of Chemistry, University of Nebraska-Lincoln, Lincoln, NE 68588 USA
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  • For correspondence: hashim.al.hashimi@duke.edu jyesselm@unl.edu herschla@stanford.edu david.case@rutgers.edu
Hashim M. Al-Hashimi
1Department of Chemistry, Duke University, Durham NC 27710 USA
2Department of Biochemistry, Duke University School of Medicine, Durham NC 27710 USA
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  • For correspondence: hashim.al.hashimi@duke.edu jyesselm@unl.edu herschla@stanford.edu david.case@rutgers.edu
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Abstract

Biomolecules do not fold into a single 3D structure but rather form dynamic ensembles of many inter-converting conformations1. Knowledge of dynamic ensembles is key for understanding how biomolecules fold and function, and for rationally manipulating their activities in drug discovery and synthetic biology2–4. However, solving dynamic ensembles of biomolecules at atomic resolution is a major challenge in structural biology because the information required to specify the position of all atoms in thousands of conformations in an ensemble far exceeds the information content of experimental measurements. Here we addressed the data gap and dramatically simplified and accelerated RNA ensemble determination by using structure prediction tools that leverage the growing database of RNA structures to generate a conformational library. Library refinement with NMR residual dipolar couplings enabled determination of an atomic-resolution ensemble for HIV-1 TAR as confirmed by quantum-mechanical calculations of NMR chemical shifts, comparison to a crystal structure of a substate, and through the successful redistribution of the ensemble by design using atomic mutagenesis. The ensemble provides an unprecedented view of how bulge residues cooperatively flip out and undergo sugar repuckering to allow the adjoining helices to stack. The generality of this approach will make determination of atomic-resolution RNA ensembles routine.

Competing Interest Statement

H.M.A. is advisor to and holds an ownership interest in Nymirum, an RNA-based drug discovery company. The remaining authors declare no competing interests.

Copyright 
The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. All rights reserved. No reuse allowed without permission.
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Posted May 23, 2020.
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An RNA dynamic ensemble at atomic resolution
Honglue Shi, Atul Rangadurai, Hala Abou Assi, Rohit Roy, David A. Case, Daniel Herschlag, Joseph D. Yesselman, Hashim M. Al-Hashimi
bioRxiv 2020.05.13.092981; doi: https://doi.org/10.1101/2020.05.13.092981
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An RNA dynamic ensemble at atomic resolution
Honglue Shi, Atul Rangadurai, Hala Abou Assi, Rohit Roy, David A. Case, Daniel Herschlag, Joseph D. Yesselman, Hashim M. Al-Hashimi
bioRxiv 2020.05.13.092981; doi: https://doi.org/10.1101/2020.05.13.092981

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