Modelling the structures of frameshift-stimulatory pseudoknots from representative bat coronaviruses

Area of Science:

• Virology
• Structural Biology
• Computational Biology

Background:

• Coronaviruses (CoVs) employ programmed ribosomal frameshifting, stimulated by RNA pseudoknots, to regulate viral replication.
• Bats are a major reservoir for CoVs, including those responsible for SARS, MERS, and COVID-19.
• The structural characteristics of bat-CoV frameshift-stimulatory pseudoknots are largely uncharacterized.

Purpose of the Study:

• To model the three-dimensional structures of eight representative bat-CoV frameshift-stimulatory pseudoknots.
• To compare these structures with the known SARS-CoV-2 pseudoknot to identify conserved and divergent features.
• To provide structural insights for the development of novel anti-coronaviral therapeutics targeting bat CoVs.

Main Methods:

• Utilized blind structure prediction algorithms to generate initial models.
• Employed all-atom molecular dynamics simulations to refine and analyze pseudoknot structures.
• Focused on pseudoknots representative of the sequence diversity found in bat CoVs.

Main Results:

• All modeled bat-CoV pseudoknots exhibited key similarities to the SARS-CoV-2 pseudoknot, including the presence of two distinct fold topologies.
• A conserved feature was the conformational flexibility at the junction, with or without 5' end threading.
• Differences were observed in helical content, with some pseudoknots possessing 2, 3, or 4 helices, unlike the 3-helix SARS-CoV-2 pseudoknot.

Conclusions:

• The structural models reveal conserved and variable features among bat-CoV pseudoknots.
• These findings highlight the potential of bat-CoV pseudoknots as therapeutic targets for broad-spectrum antiviral drug development.
• The generated structural models serve as a foundation for future functional and therapeutic studies.