Highly dissociative and concerted mechanism for the nicotinamide cleavage reaction in Sir2Tm enzyme suggested by ab initio QM/MM molecular dynamics simulations

Po Hu, Shenglong Wang, Yingkai Zhang

Research output: Contribution to journalArticle

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.

Original languageEnglish (US)
Pages (from-to)16721-16728
Number of pages8
JournalJournal of the American Chemical Society
Volume130
Issue number49
DOIs
StatePublished - Dec 10 2008

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Niacinamide
Molecular Dynamics Simulation
Molecular dynamics
Enzymes
Computer simulation
Cell death
Epigenomics
NAD
Lysine
Cell Death
Ions
Sampling
Proteins

ASJC Scopus subject areas

  • Chemistry(all)
  • Catalysis
  • Biochemistry
  • Colloid and Surface Chemistry

Cite this

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title = "Highly dissociative and concerted mechanism for the nicotinamide cleavage reaction in Sir2Tm enzyme suggested by ab initio QM/MM molecular dynamics simulations",
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.",
author = "Po Hu and Shenglong Wang and Yingkai Zhang",
year = "2008",
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T1 - Highly dissociative and concerted mechanism for the nicotinamide cleavage reaction in Sir2Tm enzyme suggested by ab initio QM/MM molecular dynamics simulations

AU - Hu, Po

AU - Wang, Shenglong

AU - Zhang, Yingkai

PY - 2008/12/10

Y1 - 2008/12/10

N2 - 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.

AB - 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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