ArticleJournal of the American Chemical Society2011
Catalytic mechanism of RNA backbone cleavage by ribonuclease H from quantum mechanics/molecular mechanics simulations.
Article in Journal of the American Chemical Society, 2011. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 94 papers.
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Who cites it
94 citing papers in PubMed, 189 citations in OpenAlex.
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- Conformationally gated multisite proton-coupled electron transfer in the ribonucleotide reductaseProceedings of the National Academy of Sciences of the United States of America · 2026Article
- Revisiting hydrolytic mechanisms of bacterial RNase HI: Towards clarification of single mobile MgBiophysics and physicobiology · 2026Article
- Unlocking the chemistry facilitated by enzymes that process nucleic acids using quantum mechanical and combined quantum mechanics-molecular mechanics techniques.Pure and applied chemistry. Chimie pure et appliquee · 2025Review
- FE-ToolKit: A Versatile Software Suite for Analysis of High-Dimensional Free Energy Surfaces and Alchemical Free Energy Networks.Journal of chemical information and modeling · 2025Article
- Structural basis for gene silencing by siRNAs in humans.bioRxiv : the preprint server for biology · 2024Article
- Nuclear Quantum Effects in Quantum Mechanical/Molecular Mechanical Free Energy Simulations of Ribonucleotide Reductase.Journal of the American Chemical Society · 2024Article
- Mechanistic insights into the conversion of flavin adenine dinucleotide (FAD) to 8-formyl FAD in formate oxidase: a combined experimental and in-silico study.Bioresources and bioprocessing · 2024Article
- Electronic and Nuclear Quantum Effects on Proton Transfer Reactions of Guanine-Thymine (G-T) Mispairs Using Combined Quantum Mechanical/Molecular Mechanical and Machine Learning Potentials.Molecules (Basel, Switzerland) · 2024Article
- Surface-Accelerated String Method for Locating Minimum Free Energy Paths.Journal of chemical theory and computation · 2024Article
- Probing Nonadiabaticity of Proton-Coupled Electron Transfer in Ribonucleotide Reductase.The journal of physical chemistry letters · 2024Article
- Investigating the Unbinding of Muscarinic Antagonists from the Muscarinic 3 Receptor.Journal of chemical theory and computation · 2023Article
- Catalytic mechanism and pH dependence of a methyltransferase ribozyme (MTR1) from computational enzymology.Nucleic acids research · 2023Article
- Exploring Proton-Coupled Electron Transfer at Multiple Scales.Nature computational science · 2023Article
- Direct Proton-Coupled Electron Transfer between Interfacial Tyrosines in Ribonucleotide Reductase.Journal of the American Chemical Society · 2023Article
- The Electronic Structure of Genome Editors from the First Principles.Electronic structure (Bristol, England) · 2023Article
- Distal Mutations in the β-Clamp of DNA Polymerase III* Disrupt DNA Orientation and Affect Exonuclease Activity.Journal of the American Chemical Society · 2023Article
34 more citing papers are in PubMed but not listed here.
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Authors and funding
4 authors at 2 institutions in 2 countries.
Funding
Abstract
We use quantum mechanics/molecular mechanics simulations to study the cleavage of the ribonucleic acid (RNA) backbone catalyzed by ribonuclease H. This protein is a prototypical member of a large family of enzymes that use two-metal catalysis to process nucleic acids. By combining Hamiltonian replica exchange with a finite-temperature string method, we calculate the free energy surface underlying the RNA-cleavage reaction and characterize its mechanism. We find that the reaction proceeds in two steps. In a first step, catalyzed primarily by magnesium ion A and its ligands, a water molecule attacks the scissile phosphate. Consistent with thiol-substitution experiments, a water proton is transferred to the downstream phosphate group. The transient phosphorane formed as a result of this nucleophilic attack decays by breaking the bond between the phosphate and the ribose oxygen. In the resulting intermediate, the dissociated but unprotonated leaving group forms an alkoxide coordinated to magnesium ion B. In a second step, the reaction is completed by protonation of the leaving group, with a neutral Asp132 as a likely proton donor. The overall reaction barrier of ∼15 kcal mol(-1), encountered in the first step, together with the cost of protonating Asp132, is consistent with the slow measured rate of ∼1-100/min. The two-step mechanism is also consistent with the bell-shaped pH dependence of the reaction rate. The nonmonotonic relative motion of the magnesium ions along the reaction pathway agrees with X-ray crystal structures. Proton-transfer reactions and changes in the metal ion coordination emerge as central factors in the RNA-cleavage reaction.
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