Modeling and Simulating RNA: Combining Structural, Dynamic, and Evolutionary Perspectives for Coronavirus Applications

RNA modeling and simulation differs both from protein and DNA modeling in many ways, due to RNA׳s hierarchical structure, intrinsic flexibility, and critical influence by other biomolecules in the cellular environment. With the rapidly rising success of RNA-based technology and therapeutics and severe human toll by viral infections like Covid-19, RNA research has entered the center stage. In this contribution, we illustrate how basic research in RNA structure and dynamics using coarse-grained graphs, 2D and 3D atomic molecular dynamics simulations, and evolutionary landscape analyses can contribute to the understanding of viral frameshifting mechanisms that influence viral propagation, as well as help define new therapeutic strategies against viral infections. The research is focused on the frameshifting element (FSE) of SARS-CoV-2, the infectious agent of Covid-19, a small part of the ≈30,000-nucleotide virus responsible for a key −1 programmed ribosomal frameshifting process required for correct viral protein synthesis. By modeling and analyzing the FSE׳s complex structural repertoire and dynamics involving a competing network of secondary-structural elements, and predicting mutations that alter these structures and associated transitions, we define new viable avenues for therapeutic intervention.