Kinetic Traps in RNA Folding: Targeted Design of Frameshifting Element Mutants by Thermodynamic and Kinetic Analysis of the Chikungunya Virus
Samuel Lee, Tamar Schlick
TL;DR
This paper studies how the Chikungunya virus RNA folds during protein synthesis and shows how to design mutants that avoid kinetic traps to target specific RNA structures.
Contribution
The paper introduces a computational framework for RNA design that accounts for both thermodynamic and kinetic factors to overcome kinetic traps.
Findings
The FSE’s conformation is determined by competition between thermodynamic stability and cotranslational folding kinetics.
The wildtype FSE is often trapped in simpler, less stable structures due to rapid formation during synthesis.
An iterative design approach informed by kinetic analysis can drive the FSE into target conformations.
Abstract
Chikungunya virus (CHIKV) employs a programmed ribosomal frameshifting element (FSE) to regulate the synthesis of its viral proteins, making the FSE an attractive antiviral target. Yet the structural dynamics that govern its function are complex and poorly understood, with multiple folds discovered. Through computational analysis, we suggest that the FSE’s conformation is determined by a competition between thermodynamic stability and cotranslational folding kinetics. Using an integrated computational pipeline, we map the FSE’s equilibrium landscape, revealing a thermodynamically favored pseudoknot that emerges only with sufficient flanking residues. We then use kinetic simulations to show that, for the wildtype sequence, this pseudoknot is often kinetically trapped in simpler, less stable stem loop structures that form more rapidly during synthesis. Using this information, we…
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Taxonomy
TopicsRNA and protein synthesis mechanisms · Viral Infections and Immunology Research · interferon and immune responses