ArticleJournal of the American Chemical Society2014
Quantum mechanical/molecular mechanical free energy simulations of the self-cleavage reaction in the hepatitis delta virus ribozyme.
Article in Journal of the American Chemical Society, 2014. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 43 papers.
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43 citing papers in PubMed, 76 citations in OpenAlex.
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- Probing Nonadiabaticity of Proton-Coupled Electron Transfer in Ribonucleotide Reductase.The journal of physical chemistry letters · 2024Article
- Direct Proton-Coupled Electron Transfer between Interfacial Tyrosines in Ribonucleotide Reductase.Journal of the American Chemical Society · 2023Article
- Dissociative Transition State in Hepatitis Delta Virus Ribozyme Catalysis.Journal of the American Chemical Society · 2023Article
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- Machine-Learning-Assisted Free Energy Simulation of Solution-Phase and Enzyme Reactions.Journal of chemical theory and computation · 2021Article
- Extension of the Variational Free Energy Profile and Multistate Bennett Acceptance Ratio Methods for High-Dimensional Potential of Mean Force Profile Analysis.The journal of physical chemistry. A · 2021Article
- Exploring the Minimum-Energy Pathways and Free-Energy Profiles of Enzymatic Reactions with QM/MM Calculations.The journal of physical chemistry. B · 2021Article
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- Glutamate Mediates Proton-Coupled Electron Transfer Between Tyrosines 730 and 731 inJournal of the American Chemical Society · 2021Article
- Environmental Effects on Guanine-Thymine Mispair Tautomerization Explored with Quantum Mechanical/Molecular Mechanical Free Energy Simulations.Journal of the American Chemical Society · 2020Article
- Hierarchical Markov State Model Building to Describe Molecular Processes.Journal of chemical theory and computation · 2020Article
- Examining the Mechanism of Phosphite Dehydrogenase with Quantum Mechanical/Molecular Mechanical Free Energy Simulations.Biochemistry · 2020Article
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Authors and funding
5 authors at 3 institutions in 2 countries.
Funding
Abstract
The hepatitis delta virus (HDV) ribozyme catalyzes a self-cleavage reaction using a combination of nucleobase and metal ion catalysis. Both divalent and monovalent ions can catalyze this reaction, although the rate is slower with monovalent ions alone. Herein, we use quantum mechanical/molecular mechanical (QM/MM) free energy simulations to investigate the mechanism of this ribozyme and to elucidate the roles of the catalytic metal ion. With Mg(2+) at the catalytic site, the self-cleavage mechanism is observed to be concerted with a phosphorane-like transition state and a free energy barrier of ∼13 kcal/mol, consistent with free energy barrier values extrapolated from experimental studies. With Na(+) at the catalytic site, the mechanism is observed to be sequential, passing through a phosphorane intermediate, with free energy barriers of 2-4 kcal/mol for both steps; moreover, proton transfer from the exocyclic amine of protonated C75 to the nonbridging oxygen of the scissile phosphate occurs to stabilize the phosphorane intermediate in the sequential mechanism. To explain the slower rate observed experimentally with monovalent ions, we hypothesize that the activation of the O2' nucleophile by deprotonation and orientation is less favorable with Na(+) ions than with Mg(2+) ions. To explore this hypothesis, we experimentally measure the pKa of O2' by kinetic and NMR methods and find it to be lower in the presence of divalent ions rather than only monovalent ions. The combined theoretical and experimental results indicate that the catalytic Mg(2+) ion may play three key roles: assisting in the activation of the O2' nucleophile, acidifying the general acid C75, and stabilizing the nonbridging oxygen to prevent proton transfer to it.
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