Dynamic Counterion Condensation Model Decodes Functional Dynamics of RNA Pseudoknot in SARS-CoV-2: Control of Ion-Mediated Pierced Lasso Topology.

The programmed frameshifting stimulatory element, a promising drug target for COVID-19 treatment, involves a RNA pseudoknot (PK) structure. This RNA PK facilitates frameshifting, enabling RNA viruses to translate multiple proteins from a single mRNA, which is a key strategy for their rapid evolution. Overcoming the challenges of capturing large-scale structural changes of RNA under the influence of a dynamic counterion environment (K + and Mg 2+ ), the study extended the applications of a newly developed dynamic counterion condensation (DCC) model. DCC simulations reveal potential folding pathways of this RNA PK, supported by the experimental findings obtained using optical tweezers. The study elucidates the pivotal role of Mg 2+ ions in crafting a lasso-like RNA topology, a novel RNA motif that governs dynamic transitions between the ring-opened and ring-closed states of the RNA. The pierced lasso component guided by Mg 2+ -mediated interactions orchestrates inward and outward motion fine-tuning tension on the slippery segment, a critical factor for optimizing frameshifting efficiency.