Riboswitches are short mRNA segments deputed to control gene expression in response to the selective binding of a metabolite.  Currently, over 20 classes of riboswitches are known, targeting metabolites that are either neutral or positively charged molecules, since this reduces or even favors the interaction of the metabolite with the negatively charged RNA backbone. This simple consideration has been recently questioned by the discovery of a riboswitch that targets a negatively charged fluoride anion.  This fluoride sensing riboswitch was found to activate the expression of genes that encode fluoride transporters. Besides targeting the small fluoride anion with good efficiency, this riboswitch has also remarkable halide selectivity, since no chloride binding was observed in presence of KCl. The X-ray structure of the fluoride riboswitch evidenced that the fluoride is the central unit keeping together a small cluster of three Mg2+ cations, whose coordination sphere is completed by either oxygen atoms of phosphate groups, and by water molecules, one of them acting as a bridge between two of the Mg2+ ions.The peculiar halide selectivity and the structure of the fluoride riboswitch provokes a series of questions: i) Is the small Mg2+/F�/phosphate/water cluster at the center of the riboswitch a stable entity on its own ? ii) Considering that water molecules bridging metal cations are known to be quite acidic, which is the acidity of the bridging water of the central cluster of the fluoride riboswitch ? iii) Which is the origin of the halide selectivity ? In this contribution we provide a clear explanation to the above three fundamental questions, based on static and dynamic density functional theory calculations.

Stability and halide selectivity of the fluoride riboswitch explained

248th National Meeting (2014)

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