ArticleNucleic acids research2023
Catalytic mechanism and pH dependence of a methyltransferase ribozyme (MTR1) from computational enzymology.
Article in Nucleic acids research, 2023. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 13 papers.
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Who cites it
13 citing papers in PubMed, 14 citations in OpenAlex.
- Mechanical Caging of Nucleic Acids Enabled by Light-Activated Synthetic Molecular Motors.Angewandte Chemie (International ed. in English) · 2026Article
- Origins of Reactivity in SAM-Utilizing Ribozyme SAMURI-Catalyzed RNA Alkylation.Journal of the American Chemical Society · 2026Article
- A magic methyl effect in the active site of a methyltransferase ribozyme.Nature communications · 2026Article
- Structure and catalytic activity of the SAM-utilizing ribozyme SAMURI.Nature chemical biology · 2026Article
- Site-specific ribozyme-mediated alkylation of DNA substrates.Nucleic acids research · 2026Article
- ProPrep: An Interactive and Instructional Interface for Proper Protein Preparation with AMBER.bioRxiv : the preprint server for biology · 2026Article
- Mutation-driven RRE stem-loop II conformational change induces HIV-1 nuclear export dysfunction.Nucleic acids research · 2025Article
- RNA-Puzzles Round V: blind predictions of 23 RNA structures.Nature methods · 2025Article
- The Role of General Acid Catalysis in the Mechanism of an Alkyl Transferase Ribozyme.ACS catalysis · 2024Article
- Accurately Modeling RNA Stem-Loops in an Implicit Solvent Environment.Journal of chemical information and modeling · 2024Article
- Software Infrastructure for Next-Generation QM/MM-ΔMLP Force Fields.The journal of physical chemistry. B · 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
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Authors and funding
8 authors at 3 institutions in 3 countries.
Funding
Abstract
A methyltransferase ribozyme (MTR1) was selected in vitro to catalyze alkyl transfer from exogenous O6-methylguanine (O6mG) to a target adenine N1, and recently, high-resolution crystal structures have become available. We use a combination of classical molecular dynamics, ab initio quantum mechanical/molecular mechanical (QM/MM) and alchemical free energy (AFE) simulations to elucidate the atomic-level solution mechanism of MTR1. Simulations identify an active reactant state involving protonation of C10 that hydrogen bonds with O6mG:N1. The deduced mechanism involves a stepwise mechanism with two transition states corresponding to proton transfer from C10:N3 to O6mG:N1 and rate-controlling methyl transfer (19.4 kcal·mol-1 barrier). AFE simulations predict the pKa for C10 to be 6.3, close to the experimental apparent pKa of 6.2, further implicating it as a critical general acid. The intrinsic rate derived from QM/MM simulations, together with pKa calculations, enables us to predict an activity-pH profile that agrees well with experiment. The insights gained provide further support for a putative RNA world and establish new design principles for RNA-based biochemical tools.
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