RNA Dynamics, a Regulatory Mechanism

Objetivo

Cells must adapt swiftly tCells must adapt swiftly to stress, infection, and environmental change through mechanisms that are rapid and reversible. RNA molecules are emerging as central regulators in these processes, not only through their sequence but also through their structural dynamics. Many regulatory RNAs interconvert between a dominant ground state (GS) and fleeting excited states (ES) on the microsecond–millisecond timescale. Although transient and sparsely populated, switching between these conformations alters fundamental processes such as microRNA repression, ribosome fidelity, and viral genome dimerization. Yet, it remains unknown which of these states are favoured inside cells, how highly they are populated, and how the molecular environment tips the balance between them to control biological outcomes.

The central hypothesis of DynaMech is that RNA structural dynamics act as a regulatory mechanism fine-tuned by cellular context. We will quantify GS and ES populations directly in human and bacterial cells, identify endogenous molecules that trigger conformational switching, and reconstitute these equilibria under controlled conditions to link structural transitions with function. This is enabled by an integrated strategy combining in-cell liquid-state NMR, DNP-enhanced solid-state NMR, high-throughput RNA probing, and mass spectrometry into a unified pipeline.

Through this approach, DynaMech will establish structural switching as a general principle of RNA regulation. It will redefine RNA molecules as dynamic regulatory hubs whose function depends on context-sensitive conformational ensembles. It will also provide the first broadly applicable framework for quantifying RNA equilibria and their cellular triggers. Ultimately, these insights will lay the foundation for therapeutic strategies that target RNA states with high precision, such as stabilizing inactive conformations in cancer or sensitizing bacterial ribosomes by exploiting structural switches.