Crucial Roles of Two Hydrated Mg<sup>2+</sup> Ions in Reaction Catalysis of the Pistol Ribozyme

Teplova, M.; Falschlunger, Christoph; Krasheninina, Olga; Egger, Michaela; Ren, Aiming; Patel, Dinshaw J.; Micura, Ronald

doi:10.1002/ange.201912522

Cited by 7 publications

(3 citation statements)

References 41 publications

(63 reference statements)

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“…110 Out of various metal ions, Mg 2+ has the most versatile contribution in RNA folding. Recent studies have unraveled active participation of Mg 2+ in modulating RNA's catalytic activity, 111 conformational flexibility, 112 and stability of folding intermediates. 113 In this paper, we show that a site-bound hydrated Mg 2+ is an intrinsic component of the TS of a unique RNA hairpin motif.…”

Section: Discussionmentioning

confidence: 99%

Mg²⁺ Sensing by an RNA Fragment: Role of Mg²⁺-Coordinated Water Molecules

Halder

Kumar

Valsson

et al. 2020

J. Chem. Theory Comput.

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RNA molecules selectively bind to specific metal ions to populate their functional active states making it important to understand their source of ion selectivity. In large RNA systems, metal ions interact with the RNA at multiple locations making it difficult to decipher the precise role of ions in folding. To overcome this complexity, we studied the role of different metal ions (Mg 2+ , Ca 2+ and K + ) in the folding of a small RNA hairpin motif (5 -ucCAAAga-3 ) using unbiased all-atom molecular dynamics simulations. The advantage in studying this small system is that it requires specific binding of a single metal ion to fold to its native state. We find that even for this small RNA, the folding free energy surface (FES) is multidimensional as different metal ions present in the solution can simultaneously facilitate folding. The FES shows that specific binding of a metal ion is indispensable for its folding. We further show that in addition to the negatively charged phosphate groups, spatial organization of electronegative nucleobase atoms drive the site specific binding of the metal ion. Even though the binding site cannot discriminate between different metal ions, RNA folds efficiently only in Mg 2+ solution. We show that the rigid network of Mg 2+ coordinated water molecules facilitate the formation of important interactions in the transition state. The other metal ions such as K + and Ca 2+ cannot facilitate the formation of such interactions. These results allow us to hypothesize possible metal sensing mechanisms in large metallo-riboswitches and they also provide useful insights for the design of appropriate collective variables for studying large RNA molecules using enhanced sampling methods.

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Section: Discussionmentioning

confidence: 99%

Mg²⁺ Sensing by an RNA Fragment: Role of Mg²⁺-Coordinated Water Molecules

Halder

Kumar

Valsson

et al. 2020

J. Chem. Theory Comput.

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“…Moreover, self-cleaving ribozymes can provide another example, in which the correct description of phosphate backbone stereochemistry is critical to assess correctly the reaction pathways of these mechanisms. (Teplova et al 2020). Yet another recent case is drug development that targets RNA (e.g., against viruses (Aftab et al 2020)).…”

Section: Introductionmentioning

confidence: 99%

“…One example is the torsion-angle-based dependence between the active and nonactive conformation of base pairs in some ribozyme active sites ( White et al 2018 ). Moreover, self-cleaving ribozymes can provide another example, in which the correct description of phosphate backbone stereochemistry is critical to correctly assess the reaction pathways of these mechanisms ( Teplova et al 2020 ). Yet another recent case is drug development that targets RNA (e.g., against viruses) ( Aftab et al 2020 ).…”

Section: Introductionmentioning

confidence: 99%

Evaluation of the stereochemical quality of predicted RNA 3D models in the RNA-Puzzles submissions

Carrascoza

Antczak

Miao

et al. 2021

RNA

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In silico prediction is a well-established approach to derive a general shape of an RNA molecule based on its sequence or secondary structure. This paper reports an analysis of the stereochemical quality of the RNA three-dimensional models predicted using dedicated computer programs. The stereochemistry of 1,052 RNA 3D structures, including 1,030 models predicted by fully automated and human-guided approaches within 22 RNA-Puzzles challenges and reference structures, is analysed. The evaluation is based on standards of RNA stereochemistry that the Protein Data Bank requires from deposited experimental structures. Deviations from standard bond lengths and angles, planarity or chirality are quantified. A reduction in the number of such deviations should help in the improvement of RNA 3D structure modelling approaches.

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Scaling Catalytic Contributions of Small Self‐Cleaving Ribozymes

et al. 2022

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Nucleolytic ribozymes utilize general acid-base catalysis to perform phosphodiester cleavage. In most ribozyme classes, a conserved active site guanosine is positioned to act as general base, thereby activating the 2'-OH group to attack the scissile phosphate (γ-catalysis). Here, we present an atomic mutagenesis study for the pistol ribozyme class. Strikingly, "general base knockout" by replacement of the guanine N1 atom by carbon results in only 2.7-fold decreased rate. Therefore, the common view that γ-catalysis critically depends on the N1 moiety becomes challenged. For pistol ribozymes we found that γ-catalysis is subordinate in overall catalysis, made up by two other catalytic factors (α and δ). Our approach allows scaling of the different catalytic contributions (α, β, γ, δ) with unprecedented precision and paves the way for a thorough mechanistic understanding of nucleolytic ribozymes with active site guanines.

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Crucial Roles of Two Hydrated Mg²⁺ Ions in Reaction Catalysis of the Pistol Ribozyme

Cited by 7 publications

References 41 publications

Mg²⁺ Sensing by an RNA Fragment: Role of Mg²⁺-Coordinated Water Molecules

Mg²⁺ Sensing by an RNA Fragment: Role of Mg²⁺-Coordinated Water Molecules

Evaluation of the stereochemical quality of predicted RNA 3D models in the RNA-Puzzles submissions

Scaling Catalytic Contributions of Small Self‐Cleaving Ribozymes

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Crucial Roles of Two Hydrated Mg2+ Ions in Reaction Catalysis of the Pistol Ribozyme

Cited by 7 publications

References 41 publications

Mg2+ Sensing by an RNA Fragment: Role of Mg2+-Coordinated Water Molecules

Mg2+ Sensing by an RNA Fragment: Role of Mg2+-Coordinated Water Molecules

Evaluation of the stereochemical quality of predicted RNA 3D models in the RNA-Puzzles submissions

Scaling Catalytic Contributions of Small Self‐Cleaving Ribozymes

Contact Info

Product

Resources

About

Crucial Roles of Two Hydrated Mg²⁺ Ions in Reaction Catalysis of the Pistol Ribozyme

Mg²⁺ Sensing by an RNA Fragment: Role of Mg²⁺-Coordinated Water Molecules

Mg²⁺ Sensing by an RNA Fragment: Role of Mg²⁺-Coordinated Water Molecules