Structural stability, acidity, and halide selectivity of the fluoride riboswitch recognition site

Using static and dynamics DFT methods we show that the Mg2+/F-/phosphate/water cluster at the center of the fluoride riboswitch is stable by its own and, once assembled, does not rely on any additional factor from the overall RNA fold. Further, we predict that the pKa of the water molecule bridging two Mg cations is around 8.4. We also demonstrate that the halide selectivity of the fluoride riboswitch is determined by the stronger Mg-F bond, which is capable of keeping together the cluster. Replacing F- with Cl- results in a cluster that is unstable under dynamic conditions. Similar conclusions on the structure and energetics of the cluster in the binding pocket of fluoride-inhibited pyrophosphatase suggest that the peculiarity of fluoride is in its ability to establish much stronger metal-halide bonds.

Chawla, M., Credendino, R., Poater, A., Oliva, R., & Cavallo, L. (2014). Structural Stability, Acidity, and Halide Selectivity of the Fluoride Riboswitch Recognition Site. Journal of the American Chemical Society, 137(1), 299–306. doi:10.1021/ja510549b

We thank one of the reviewers for suggesting us to model the pyrophosphatase system. Research reported in this publication was supported by the King Abdullah University of Science and Technology. We thank the HPC team of Enea ( for generous access to the ENEA-GRID and the HPC facilities CRESCO ( in Portici, Italy. A.P. thanks the Spanish MINECO for a Ramon y Cajal contract (RYC-2009-05226) and European Commission for a Career Integration Grant (CIG09-GA-2011-293900).

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Journal of the American Chemical Society


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