Catalytic mechanism and product specificity of the histone lysine methyltransferase SET7/9: An ab initio QM/MM-FE study with multiple initial structures

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Abstract

Histone lysine methylation is emerging as an important mechanism to regulate chromatin structure and gene activity. To provide theoretical understanding of its reaction mechanism and product specificity, ab initio quantum mechanical/molecular mechanical free energy (QM/MM-FE) calculations and molecular dynamics simulations have been carried out to investigate the histone lysine methyltransferase SET7/9. It is found that the methyl-transfer reaction catalyzed by SET7/9 is a typical in-line S N2 nucleophilic substitution reaction with a transition state of 70% dissociative character. The calculated average free energy barrier at the MP2(6-31+G*) QM/MM level is 20.4 ± 1.1 kcal/mol, consistent with the activation barrier of 20.9 kcal/mol estimated from the experimental reaction rate. The barrier fluctuation has a strong correlation with the nucleophilic attack distance and angle in the reactant complex. The calculation results show that the product specificity of SET7/9 as a monomethyltransferase is achieved by disrupting the formation of near-attack conformations for the dimethylation reaction.

Original languageEnglish (US)
Pages (from-to)1272-1278
Number of pages7
JournalJournal of the American Chemical Society
Volume128
Issue number4
DOIs
StatePublished - Feb 1 2006

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Histone-Lysine N-Methyltransferase
Molecular Dynamics Simulation
Histones
Methylation
Free energy
Lysine
Chromatin
Energy barriers
Genes
Reaction rates
Conformations
Molecular dynamics
Substitution reactions
Chemical activation
Computer simulation

ASJC Scopus subject areas

  • Chemistry(all)

Cite this

@article{5de77a55bc4d4a3ea995da08e628446c,
title = "Catalytic mechanism and product specificity of the histone lysine methyltransferase SET7/9: An ab initio QM/MM-FE study with multiple initial structures",
abstract = "Histone lysine methylation is emerging as an important mechanism to regulate chromatin structure and gene activity. To provide theoretical understanding of its reaction mechanism and product specificity, ab initio quantum mechanical/molecular mechanical free energy (QM/MM-FE) calculations and molecular dynamics simulations have been carried out to investigate the histone lysine methyltransferase SET7/9. It is found that the methyl-transfer reaction catalyzed by SET7/9 is a typical in-line S N2 nucleophilic substitution reaction with a transition state of 70{\%} dissociative character. The calculated average free energy barrier at the MP2(6-31+G*) QM/MM level is 20.4 ± 1.1 kcal/mol, consistent with the activation barrier of 20.9 kcal/mol estimated from the experimental reaction rate. The barrier fluctuation has a strong correlation with the nucleophilic attack distance and angle in the reactant complex. The calculation results show that the product specificity of SET7/9 as a monomethyltransferase is achieved by disrupting the formation of near-attack conformations for the dimethylation reaction.",
author = "Po Hu and Yingkai Zhang",
year = "2006",
month = "2",
day = "1",
doi = "10.1021/ja056153+",
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volume = "128",
pages = "1272--1278",
journal = "Journal of the American Chemical Society",
issn = "0002-7863",
publisher = "American Chemical Society",
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T1 - Catalytic mechanism and product specificity of the histone lysine methyltransferase SET7/9

T2 - An ab initio QM/MM-FE study with multiple initial structures

AU - Hu, Po

AU - Zhang, Yingkai

PY - 2006/2/1

Y1 - 2006/2/1

N2 - Histone lysine methylation is emerging as an important mechanism to regulate chromatin structure and gene activity. To provide theoretical understanding of its reaction mechanism and product specificity, ab initio quantum mechanical/molecular mechanical free energy (QM/MM-FE) calculations and molecular dynamics simulations have been carried out to investigate the histone lysine methyltransferase SET7/9. It is found that the methyl-transfer reaction catalyzed by SET7/9 is a typical in-line S N2 nucleophilic substitution reaction with a transition state of 70% dissociative character. The calculated average free energy barrier at the MP2(6-31+G*) QM/MM level is 20.4 ± 1.1 kcal/mol, consistent with the activation barrier of 20.9 kcal/mol estimated from the experimental reaction rate. The barrier fluctuation has a strong correlation with the nucleophilic attack distance and angle in the reactant complex. The calculation results show that the product specificity of SET7/9 as a monomethyltransferase is achieved by disrupting the formation of near-attack conformations for the dimethylation reaction.

AB - Histone lysine methylation is emerging as an important mechanism to regulate chromatin structure and gene activity. To provide theoretical understanding of its reaction mechanism and product specificity, ab initio quantum mechanical/molecular mechanical free energy (QM/MM-FE) calculations and molecular dynamics simulations have been carried out to investigate the histone lysine methyltransferase SET7/9. It is found that the methyl-transfer reaction catalyzed by SET7/9 is a typical in-line S N2 nucleophilic substitution reaction with a transition state of 70% dissociative character. The calculated average free energy barrier at the MP2(6-31+G*) QM/MM level is 20.4 ± 1.1 kcal/mol, consistent with the activation barrier of 20.9 kcal/mol estimated from the experimental reaction rate. The barrier fluctuation has a strong correlation with the nucleophilic attack distance and angle in the reactant complex. The calculation results show that the product specificity of SET7/9 as a monomethyltransferase is achieved by disrupting the formation of near-attack conformations for the dimethylation reaction.

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