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Published on: September 7, 2022
Enhanced-sampling simulations reveal distinct intermediates in SARS-CoV-2 FSE pseudoknot interconversion
Karim Malekzadeh1, Mangesh Bhendale1, Gül H Zerze2
1William A. Brookshire Department of Chemical and Biomolecular Engineering, University of Houston, Houston, TX, USA.
Biophysical Journal
|July 3, 2026
Summary
The SARS-CoV-2 frameshifting stimulatory element (FSE) can adopt multiple structures, influencing viral protein synthesis. This study reveals the pathways and intermediates involved in transitions between these FSE structures.
Area of Science:
- Molecular Biology
- Virology
- Computational Biology
Background:
- The SARS-CoV-2 frameshifting stimulatory element (FSE) is crucial for viral protein synthesis via programmed -1 ribosomal frameshifting.
- The FSE is a known target for antiviral therapies.
- The FSE is structurally heterogeneous, adopting alternative conformations that influence frameshifting efficiency.
Purpose of the Study:
- To investigate the transition pathways between alternative structures of the SARS-CoV-2 FSE.
- To understand the role of conformational plasticity in FSE function.
- To identify structural intermediates during FSE structural rearrangements.
Main Methods:
- Atomistic resolution molecular dynamics simulations using the Multithermal-Multiumbrella On-the-Fly Probability Enhanced Sampling (MM-OPES) technique.
- Sampling interconversions between two H-type 3-stem pseudoknots (motifs 3_3 and 3_6) of the SARS-CoV-2 FSE.
- Free-energy calculations and trajectory analysis to identify transition pathways and intermediates.
Main Results:
- Well-defined free-energy basins for motifs 3_3 and 3_6 were identified, along with intermediate regions.
- Distinct terminal-segment-mediated contacts were observed during interconversions.
- Trajectories revealed stepwise and concurrent transition routes, including transient triplex-like interactions and metastable intermediates stabilized by non-native contacts.
Conclusions:
- The study elucidates the molecular mechanisms underlying SARS-CoV-2 FSE conformational plasticity.
- Identified structural intermediates and contact rearrangements provide insights into frameshifting efficiency modulation.
- Understanding these pathways can inform the design of novel antiviral strategies targeting FSE structure.
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