ArticleJournal of the American Chemical Society2008
Highly dissociative and concerted mechanism for the nicotinamide cleavage reaction in Sir2Tm enzyme suggested by ab initio QM/MM molecular dynamics simulations.
Article in Journal of the American Chemical Society, 2008. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 34 papers.
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34 citing papers in PubMed, 79 citations in OpenAlex.
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- NMR solution structures of Runella slithyformis RNA 2'-phosphotransferase Tpt1 provide insights into NAD+ binding and specificity.Nucleic acids research · 2021Article
- Intrinsic Cleavage of RNA Polymerase II Adopts a Nucleobase-independent Mechanism Assisted by Transcript Phosphate.Nature catalysis · 2019Article
- Solvation Free Energy Calculations with Quantum Mechanics/Molecular Mechanics and Machine Learning Models.The journal of physical chemistry. B · 2019Article
- Molecular Dynamics Simulations with Quantum Mechanics/Molecular Mechanics and Adaptive Neural Networks.Journal of chemical theory and computation · 2018Article
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- Internal force corrections with machine learning for quantum mechanics/molecular mechanics simulations.The Journal of chemical physics · 2017Article
- Thiol versus hydroxamate as zinc binding group in HDAC inhibition: An ab initio QM/MM molecular dynamics study.Journal of computational chemistry · 2015Article
- How is acetylcholinesterase phosphonylated by soman? An ab initio QM/MM molecular dynamics study.The journal of physical chemistry. A · 2014Article
- Mechanism of inhibition of the human sirtuin enzyme SIRT3 by nicotinamide: computational and experimental studies.PloS one · 2014Article
- DNA cytosine methylation: structural and thermodynamic characterization of the epigenetic marking mechanism.Biochemistry · 2013Article
- Sirtuin Deacetylation Mechanism and Catalytic Role of the Dynamic Cofactor Binding Loop.The journal of physical chemistry letters · 2013Article
- Aging mechanism of soman inhibited acetylcholinesterase.The journal of physical chemistry. B · 2012Article
- Preferred WMSA catalytic mechanism of the nucleotidyl transfer reaction in human DNA polymerase κ elucidates error-free bypass of a bulky DNA lesion.Nucleic acids research · 2012Article
- Revelation of a catalytic calcium-binding site elucidates unusual metal dependence of a human apyrase.Journal of the American Chemical Society · 2012Article
- Azalysine analogues as probes for protein lysine deacetylation and demethylation.Journal of the American Chemical Society · 2012Article
- Insights into the phosphoryl transfer mechanism of cyclin-dependent protein kinases from ab initio QM/MM free-energy studies.The journal of physical chemistry. B · 2011Article
- Insight into the phosphodiesterase mechanism from combined QM/MM free energy simulations.The FEBS journal · 2011Article
- Zinc chelation with hydroxamate in histone deacetylases modulated by water access to the linker binding channel.Journal of the American Chemical Society · 2011Article
- Ab initio QM/MM free-energy studies of arginine deiminase catalysis: the protonation state of the Cys nucleophile.The journal of physical chemistry. B · 2011Article
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Authors and funding
3 authors at 1 institution in 1 country.
Funding
Abstract
Sir2 enzymes catalyze the NAD+-dependent protein deacetylation and play critical roles in epigenetics, cell death, and lifespan regulation. In spite of a current flurry of experimental studies, the catalytic mechanism for this unique and important class of enzymes remains elusive. Employing on-the-fly Born-Oppenheimer molecular dynamics simulations with the B3LYP/6-31G(d) QM/MM potential and the umbrella sampling method, we have characterized the initial step of the Sir2Tm-catalyzed reaction, which is also the most controversial portion of its mechanism. Our results indicate that the nicotinamide cleavage reaction employs a highly dissociative and concerted displacement mechanism: the cleavage of the glycosidic bond is facilitated by the nucleophilic participation of the acetyl-lysine, and the dissociative transition state has a significant oxocarbenium ion character. During this step of the reaction, the Sir2Tm enzyme strongly stabilizes the covalent O-alkylamidate intermediate whereas its effect on the transition state is quite minimal. In addition, functional roles of key residues and motifs have been elucidated. This work further demonstrates the feasibility and applicability of the state-of-the-art ab initio QM/MM molecular dynamics approach in simulating enzyme reactions.
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