SARS-CoV-2 ribosomal frameshifting pseudoknot: Improved secondary structure prediction and detection of inter-viral structural similarity

A bstract

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has led to the COVID-19 pandemic; a pandemic of a scale that has not been seen in the modern era. Despite over 29 million reported cases and over 900, 000 deaths worldwide as of September 2020, herd immunity and widespread vaccination efforts by many experts are expected to be insufficient in addressing this crisis for the foreseeable future. Thus, there is an urgent need for treatments that can lessen the effects of SARS-CoV-2 in patients who become seriously affected. Many viruses including HIV, the common cold, SARS-CoV and SARS-CoV-2 use a unique mechanism known as −1 programmed ribosomal frameshifting (−1 PRF) to successfully replicate and infect cells in the human host. SARS-CoV (the coronavirus responsible for SARS) and SARS-CoV-2 possess a unique RNA structure, a three-stemmed pseudoknot, that stimulates −1 PRF. Recent experiments identified that small molecules can be introduced as antiviral agents to bind with the pseudoknot and disrupt its stimulation of −1 PRF. If successfully developed, small molecule therapy that targets −1 PRF in SARS-CoV-2 is an excellent strategy to improve patients’ prognoses. Crucial to developing these successful therapies is modeling the structure of the SARS-CoV-2 −1 PRF pseudoknot. Following a structural alignment approach, we identify similarities in the −1 PRF pseudoknots of the novel coronavirus SARS-CoV-2, the original SARS-CoV, as well as a third coronavirus: MERS-CoV, the coronavirus responsible for Middle East Respiratory Syndrome (MERS). In addition, we provide a better understanding of the SARS-CoV-2 −1 PRF pseudoknot by comprehensively investigating the structural landscape using a hierarchical folding approach. Since understanding the impact of mutations is vital to long-term success of treatments that are based on predicted RNA functional structures, we provide insight on SARS-CoV-2 −1 PRF pseudoknot sequence mutations and their effect on the resulting structure and its function.