(360av) A Computational Study for Predicting Stability Differences in Multiple Conformations of the Sars-Cov?2 Frameshifting RNA Element

Pseudoknotted RNA structural elements stimulate the frameshifting process during protein translation. The RNA pseudoknot that causes ribosomal frameshifting in SARS-CoV-2 is a potential drug target for fighting against Covid-19. This small part of RNA programs translational frameshifting during the translation of RNA from Open Reading Frame (ORF) 1a upstream to 1b downstream. Viral polyproteins which are produced in this process are essential in viral replication and any interference in this process, including structural modifications, will alter virus replication rates. Recent advances
in this area for predicting two-dimensional (2D) structures have shown that the frameshifting element can take multiple conformations [1]. Despite this progress in structure prediction, we still lack an important piece of information: stability differences between 3D structures of this molecule. In an effort to address that computationally, in this work, we have adapted our recently developed technique [2] to calculate the free energy surface of 13469−13545(77 nt) of SARS-CoV-2 RNA to measure the free-energetic competition between 3-stem H-type pseudoknot (3_6) and HL-type 3-stem pseudoknot (3_3) by using a combined parallel tempering and metadynamics technique.

[1] Zerze, Gül H., Pablo M. Piaggi, and Pablo G. Debenedetti. “A Computational Study of RNA Tetraloop Thermodynamics, Including Misfolded States.” The Journal of Physical Chemistry B 125.50 (2021): 13685-13695.

[2] Schlick, Tamar, et al. "To knot or not to knot: Multiple conformations of the SARS-CoV-2 frameshifting RNA element." Journal of the American Chemical Society 143.30 (2021): 11404-11422.