Modeling the structure of the frameshift-stimulatory pseudoknot in SARS-CoV-2 reveals multiple possible conformers

Sara Ibrahim Omar; Meng Zhao; Rohith Vedhthaanth Sekar; Sahar Arbabi Moghadam; Jack A Tuszynski; Michael T Woodside

doi:10.1371/journal.pcbi.1008603

Modeling the structure of the frameshift-stimulatory pseudoknot in SARS-CoV-2 reveals multiple possible conformers

PLoS Comput Biol. 2021 Jan 19;17(1):e1008603. doi: 10.1371/journal.pcbi.1008603. eCollection 2021 Jan.

Authors

Sara Ibrahim Omar^{1

2}, Meng Zhao¹, Rohith Vedhthaanth Sekar¹, Sahar Arbabi Moghadam¹, Jack A Tuszynski^{1

2}, Michael T Woodside¹

Affiliations

¹ Department of Physics, University of Alberta, Edmonton, Alberta, Canada.
² Department of Oncology, University of Alberta, Edmonton, Alberta, Canada.

Abstract

The coronavirus causing the COVID-19 pandemic, SARS-CoV-2, uses -1 programmed ribosomal frameshifting (-1 PRF) to control the relative expression of viral proteins. As modulating -1 PRF can inhibit viral replication, the RNA pseudoknot stimulating -1 PRF may be a fruitful target for therapeutics treating COVID-19. We modeled the unusual 3-stem structure of the stimulatory pseudoknot of SARS-CoV-2 computationally, using multiple blind structural prediction tools followed by μs-long molecular dynamics simulations. The results were compared for consistency with nuclease-protection assays and single-molecule force spectroscopy measurements of the SARS-CoV-1 pseudoknot, to determine the most likely conformations. We found several possible conformations for the SARS-CoV-2 pseudoknot, all having an extended stem 3 but with different packing of stems 1 and 2. Several conformations featured rarely-seen threading of a single strand through junctions formed between two helices. These structural models may help interpret future experiments and support efforts to discover ligands inhibiting -1 PRF in SARS-CoV-2.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

COVID-19 / virology
Computational Biology
Frameshifting, Ribosomal*
Humans
Nucleic Acid Conformation*
SARS-CoV-2 / chemistry*
SARS-CoV-2 / genetics

Grants and funding

Funding was received for this work by MTW and JAT from the Canadian Institutes of Health Research (https://cihr-irsc.gc.ca/e/193.html), reference no. OV3–170709, and from Alberta Innovates (https://albertainnovates.ca/), reference no. G2020000270. The funders had no role in the study design, data collection and analysis, decision to publish, or preparation of the manuscript.