Structure-altering mutations of the SARS-CoV-2 frameshifting RNA element

Area of Science:

• Computational biology
• Virology
• RNA structure and function

Background:

• The urgent need for COVID-19 treatments necessitates exploring therapeutic targets beyond proteins.
• The viral RNA genome presents a promising complementary target for drug and vaccine development.
• Ribosomal frameshifting, mediated by the RNA frameshifting element (FSE), is crucial for SARS-CoV-2 replication.

Purpose of the Study:

• To computationally design mutations targeting the SARS-CoV-2 FSE, specifically its pseudoknot structure.
• To investigate the potential of disrupting viral translation through FSE structural alterations.
• To identify key viral residues for novel antiviral therapeutic strategies.

Main Methods:

• Application of the RNA-As-Graphs (RAG) framework for RNA secondary structure representation.
• Utilizing genetic algorithms for inverse folding to predict minimal mutations in the FSE.
• Employing microsecond molecular dynamics simulations to assess the stability of mutant RNA structures.

Main Results:

• Computationally predicted minimal mutations capable of disrupting essential structural features of the SARS-CoV-2 FSE.
• Demonstrated relative stability of mutated RNA secondary structures via molecular dynamics simulations.
• Identified key residues within the FSE critical for viral translation.

Conclusions:

• The RAG framework facilitates the computational design of RNA structures, including those with pseudoknots.
• Disrupting the SARS-CoV-2 FSE structure is a viable strategy for inhibiting viral replication.
• Key residues in the FSE are potential targets for developing new antiviral drugs and gene editing therapies.