Length-dependent motions of SARS-CoV-2 frameshifting RNA pseudoknot and alternative conformations suggest avenues for frameshifting suppression
Conserved SARS-CoV-2 RNA regions of critical biological functions define excellent targets for anti-viral therapeutics against Covid-19 variants. One such region is the frameshifting element (FSE), responsible for correct translation of viral polyproteins. Here, we analyze molecular-dynamics motions of three FSE conformations, discovered by graph-theory analysis, and associated mutants designed by graph-based inverse folding: two distinct 3-stem H-type pseudoknots and a 3-way junction. We find that the prevalent H-type pseudoknot in literature adopts ring-like conformations, which in combination with 5' end threading could promote ribosomal pausing. An inherent shape switch from "L" to linear that may help trigger the frameshifting is suppressed in our designed mutant. The alternative conformation trajectories suggest a stable intermediate structure with mixed stem interactions of all three conformations, pointing to a possible transition pathway during ribosomal translation. These observations provide new insights into anti-viral strategies and frameshifting mechanisms.
| Errataetall: |
UpdateIn: Nat Commun. 2022 Jul 25;13(1):4284. - PMID 35879278 |
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| Medienart: |
E-Artikel |
| Erscheinungsjahr: |
2022 |
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| Erschienen: |
2022 |
| Enthalten in: |
Zur Gesamtaufnahme - year:2022 |
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| Enthalten in: |
Research square - (2022) vom: 04. Jan. |
| Sprache: |
Englisch |
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| Beteiligte Personen: |
Yan, Shuting [VerfasserIn] |
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Date Revised 05.04.2024 published: Electronic UpdateIn: Nat Commun. 2022 Jul 25;13(1):4284. - PMID 35879278 Citation Status PubMed-not-MEDLINE |
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| doi: |
10.21203/rs.3.rs-1160075/v1 |
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| funding: |
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| 500 | |a UpdateIn: Nat Commun. 2022 Jul 25;13(1):4284. - PMID 35879278 | ||
| 500 | |a Citation Status PubMed-not-MEDLINE | ||
| 520 | |a Conserved SARS-CoV-2 RNA regions of critical biological functions define excellent targets for anti-viral therapeutics against Covid-19 variants. One such region is the frameshifting element (FSE), responsible for correct translation of viral polyproteins. Here, we analyze molecular-dynamics motions of three FSE conformations, discovered by graph-theory analysis, and associated mutants designed by graph-based inverse folding: two distinct 3-stem H-type pseudoknots and a 3-way junction. We find that the prevalent H-type pseudoknot in literature adopts ring-like conformations, which in combination with 5' end threading could promote ribosomal pausing. An inherent shape switch from "L" to linear that may help trigger the frameshifting is suppressed in our designed mutant. The alternative conformation trajectories suggest a stable intermediate structure with mixed stem interactions of all three conformations, pointing to a possible transition pathway during ribosomal translation. These observations provide new insights into anti-viral strategies and frameshifting mechanisms | ||
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