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Structured RNAs such as ribozymes must fold into specific 3D structures to carry out their biological functions. While it is well-known that architectural features such as flexible junctions between helices help guide RNA tertiary folding, the mechanisms through which junctions influence folding remain poorly understood. We combine computational modeling with single molecule Förster resonance energy transfer (smFRET) and catalytic activity measurements to investigate the influence of junction design on the folding and function of the hairpin ribozyme. Coarse-grained simulations of a wide range of junction topologies indicate that differences in sterics and connectivity, independent of stacking, significantly affect tertiary folding and appear to largely explain previously observed variations in hairpin ribozyme stability. We further use our simulations to identify stabilizing modifications of non-optimal junction topologies, and experimentally validate that a three-way junction variant of the hairpin ribozyme can be stabilized by specific insertion of a short single-stranded linker. Combined, our multi-disciplinary study further reinforces that junction sterics and connectivity are important determinants of RNA folding, and demonstrates the potential of coarse-grained simulations as a tool for rationally tuning and optimizing RNA folding and function.

Tuning RNA folding and function through rational design of junction topology