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Abolished frameshifting for predicted structure-stabilizing SARS-CoV-2 mutants: implications to alternative
Abhishek Dey1, Shuting Yan2, Tamar Schlick2,3,4,5
1Department of Biotechnology, National Institute of Pharmaceutical Education and Research (NIPER-R)-Raebareli, Lucknow 226002, India rf.abhishek.dey@niperrbl.ac.in.
RNA (New York, N.Y.)
|July 31, 2024
Summary
Mutant SARS-CoV-2 frameshifting elements (FSEs) were designed to suppress structural transitions, abolishing frameshifting. This confirms alternative RNA conformations are crucial for ribosomal transitions in SARS-CoV-2.
Area of Science:
- Molecular Biology
- Virology
- RNA Structure and Dynamics
Background:
- The SARS-CoV-2 frameshifting element (FSE) is a key therapeutic target for COVID-19.
- FSEs exhibit diverse length-dependent conformations, but their role in frameshifting remains unclear.
Purpose of the Study:
- To investigate the functional significance of alternative RNA conformations in SARS-CoV-2 FSEs.
- To explore methods for quantifying RNA structural abundance and its impact on frameshifting.
Main Methods:
- Utilized dimethyl sulfate (DMS) and dual-luciferase functional assays.
- Employed RAG graph theory for mutant prediction.
- Applied correlated mutation analysis using DREEM, DRACO, and DANCE-MaP programs.
Main Results:
- Predicted FSE mutants suppressed structural transitions and abolished frameshifting.
- Different computational programs showed variations in estimating specific RNA conformations.
- Abolished frameshifting in mutants confirmed the role of alternative conformations in ribosomal transitions.
Conclusions:
- Alternative RNA conformations are essential for the SARS-CoV-2 frameshifting mechanism.
- Caution is advised when interpreting complex RNA conformational landscapes from computational analyses.
- Targeting FSE structural dynamics offers potential therapeutic strategies against coronaviruses.
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