Title:  The SARS-CoV-2 Frame Shifting RNA Element: Structures, dynamics, and evolution
Abstract:  Due to the high sequence conservation of the SARS-CoV-2 viral genome, its close evolutionary relationship to other viruses, and the rise of gene editing and RNA-based vaccines, studies focused on the RNA genome form a complement to work focusing on the viral proteins. Here we apply our graph-theory-based framework for representing RNA secondary structures ``RAG" (RNA-As Graphs) to study structural, dynamic, and evolutionary features of the frame-shifting element (FSE) of the SARS-CoV-2 virus, one of three highly conserved regions of coronaviruses. A key aspect of ribosomal frameshifting is a bulky pseudoknot structure for the associated RNA. Using RAG-based machinery for studying conformational landscapes as a function of RNA sequence length and genetic algorithms for inverse folding adapted for pseudoknots, we model FSE structures, dynamics, and evolutionary behavior, as well as computationally predict minimal mutations that alter FSE structures. These studies not only advance our computational techniques for modeling RNAs containing pseudoknots; they suggest how FSE structures have evolved and might further evolve, and pinpoint to key residues of the virus as targets for anti-viral drugs and gene editing approaches.