Molecular simulations of the pistol ribozyme: unifying the interpretation of experimental data and establishing functional links with the hammerhead ribozyme

RNA
Ken Kostenbader, Darrin M York

Abstract

The pistol ribozyme (Psr) is among the most recently discovered RNA enzymes and has been the subject of experiments aimed at elucidating the mechanism. Recent biochemical studies have revealed exciting clues about catalytic interactions in the active site not apparent from available crystallographic data. The present work unifies the interpretation of the existing body of structural and functional data on Psr by providing a dynamical model for the catalytically active state in solution from molecular simulation. Our results suggest that a catalytic Mg2+ ion makes inner-sphere contact with G33:N7 and outer-sphere coordination to the pro-RP of the scissile phosphate, promoting electrostatic stabilization of the dianionic transition state and neutralization of the developing charge of the leaving group through a metal-coordinated water molecule that is made more acidic by a hydrogen bond donated from the 2'OH of P32. This model is consistent with experimental activity-pH and mutagenesis data, including sensitivity to G33(7cG) and phosphorothioate substitution/metal ion rescue. The model suggests several experimentally testable predictions, including the response of cleavage activity to mutations at G42 and P32 positions in the rib...Continue Reading

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Citations

Apr 29, 2020·The Journal of Physical Chemistry. B·Hung T Nguyen, Devarajan Thirumalai
May 27, 2020·The Journal of Physical Chemistry. B·Narendra Kumar, Dominik Marx

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