{"doi":"10.1371/journal.pcbi.1008603","title":"Modeling the structure of the frameshift-stimulatory pseudoknot in SARS-CoV-2 reveals multiple possible conformers","abstract":"<jats:p>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.</jats:p>","journal":"PLOS Computational Biology","year":2021,"id":610266,"datarank":0.5955437870328184,"base_score":3.970291913552122,"endowment":3.970291913552122,"self_citation_contribution":0.5955437870328184,"citation_network_contribution":0.0,"self_endowment_contribution":0.5955437870328184,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":52,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":null,"is_data_producer":false,"deposit_databanks":null,"is_oa":false,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":null,"fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":763091,"name":"Meng Zhao","orcid":"0000-0001-6392-4954","position":1,"is_corresponding":false},{"id":1569009,"name":"Rohith Vedhthaanth Sekar","orcid":"0000-0003-3581-8016","position":2,"is_corresponding":false},{"id":1569010,"name":"Sahar Arbabi Moghadam","orcid":"0000-0002-4781-6184","position":3,"is_corresponding":false},{"id":1294205,"name":"Jack A. Tuszyński","orcid":"0000-0001-9976-0429","position":4,"is_corresponding":false},{"id":240543,"name":"Michael T. Woodside","orcid":"0000-0003-4695-0397","position":5,"is_corresponding":false},{"id":1569008,"name":"Sara Ibrahim Omar","orcid":"0000-0002-0133-3531","position":0,"is_corresponding":false}],"reference_count":0,"raw_metadata":{"has_enrichment":true,"resolved":true,"title":"Modeling the structure of the frameshift-stimulatory pseudoknot in SARS-CoV-2 reveals multiple possible conformers","abstract":"<jats:p>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.</jats:p>","is_dataset_classified":null,"base_score":3.970291913552122,"endowment":3.970291913552122,"datacite_reuse_total":0,"file_count":0,"downloads":0,"views":0,"has_version_chain":false,"is_dataset":false,"is_oa":false,"pmid":"33465066","pmcid":"PMC7845960","openalex_id":"https://openalex.org/W3122439967","authors":[],"funders":[{"funder_name":"Canadian Institutes of Health Research","grant_id":"OV3–170709","title":null},{"funder_name":"Alberta Innovates","grant_id":"G2020000270","title":null}],"total_grants":2,"fwci":2.7251,"citation_percentile":0.92257569,"influential_citations":0,"citation_trend":[{"year":2020,"count":4},{"year":2021,"count":15},{"year":2022,"count":14},{"year":2023,"count":10},{"year":2024,"count":5},{"year":2025,"count":3},{"year":2026,"count":1}],"oa_status":"gold","license":"cc-by","oa_locations":[{"url":"https://journals.plos.org/ploscompbiol/article/file?id=10.1371/journal.pcbi.1008603&type=printable","host_type":"journal"},{"url":"https://journals.plos.org/ploscompbiol/article/file?id=10.1371/journal.pcbi.1008603&type=printable","host_type":"publisher"},{"url":"https://dx.plos.org/10.1371/journal.pcbi.1008603","host_type":"publisher"},{"url":"https://doi.org/10.1371/journal.pcbi.1008603","host_type":"journal"},{"url":"https://pubmed.ncbi.nlm.nih.gov/33465066","host_type":"repository"},{"url":"https://journals.plos.org/ploscompbiol/article?id=10.1371/journal.pcbi.1008603","host_type":"repository"},{"url":"https://doaj.org/article/6c334b817bc846da905ffdeb82ddcbaf","host_type":"repository"},{"url":"http://europepmc.org/pmc/articles/PMC7845960","host_type":"repository"},{"url":"https://www.ncbi.nlm.nih.gov/pmc/articles/7845960","host_type":"repository"},{"url":"https://europepmc.org/articles/PMC7845960","host_type":"Europe_PMC"},{"url":"https://europepmc.org/articles/PMC7845960?pdf=render","host_type":"Europe_PMC"}],"fields_of_study":["SARS-CoV-2 and COVID-19 Research","Infectious Encephalopathies and Encephalitis","Influenza Virus Research Studies"],"mesh_terms":["COVID-19","SARS-CoV-2","Humans","Nucleic Acid Conformation","Frameshifting, Ribosomal","Computational Biology"],"keywords":["Pseudoknot","Conformational isomerism","Frameshift mutation","Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)","Coronavirus disease 2019 (COVID-19)","2019-20 coronavirus outbreak","Computational biology","Biology","Statistical physics","Physics","Medicine","Virology","Base sequence","Genetics","Mutation"],"sdg_mappings":[{"sdg_number":0,"sdg_label":"Good health and well-being"}],"linked_datasets":[],"clinical_trials":[],"software_tools":[],"database_accessions":[],"source":"live","citation_network_status":"fetched"},"created_at":"2026-07-31T20:56:39.831461Z","pmid":null,"pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}