Rapid and accurate determination of atomistic RNA dynamic ensemble models using NMR and structure prediction

Authors

Honglue Shi, Duke University, Durham & Duke University School of Medicine, Durham
Atul Rangadurai, Duke University School of Medicine, Durham
Hala Abou Assi, Duke University School of Medicine, Durham
Rohit Roy, Duke University School of Medicine, Durham
David A. Case, Rutgers University, PiscatawayFollow
Daniel Herschlag, Stanford University, StanfordFollow
Joseph D. Yesselman, University of Nebraska - LincolnFollow
Hashim M. Al-Hashimi, Duke University, DurhamFollow

ORCID IDs

http://orcid.org/0000-0003-3847-1652

http://orcid.org/0000-0003-0681-1747

Date of this Version

2020

Citation

NATURE COMMUNICATIONS | (2020)11:5531 | https://doi.org/10.1038/s41467-020-19371-y | www.nature.com/naturecommunications

Comments

The Author(s) 2020

Abstract

Biomolecules form dynamic ensembles of many inter-converting conformations which are key for understanding how they fold and function. However, determining ensembles is challenging because the information required to specify atomic structures for thousands of conformations far exceeds that of experimental measurements. We addressed this 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 con- formation library. Refinement of this library with NMR residual dipolar couplings provided an atomistic ensemble model for HIV-1 TAR, and the model accuracy was independently sup- ported by comparisons to quantum-mechanical calculations of NMR chemical shifts, com- parison to a crystal structure of a substate, and through designed ensemble redistribution via atomic mutagenesis. Applications to TAR bulge variants and more complex tertiary RNAs support the generality of this approach and the potential to make the determination of atomic-resolution RNA ensembles routine.