Catalytic Mechanism and Product Specificity of the Histone Lysine Methyltransferase SET7/9: An ab Initio QM/MM-FE Study with Multiple Initial Structures
- 6 January 2006
- journal article
- research article
- Published by American Chemical Society (ACS) in Journal of the American Chemical Society
- Vol. 128 (4), 1272-1278
- https://doi.org/10.1021/ja056153+
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 SN2 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.This publication has 32 references indexed in Scilit:
- Conformational Substates Modulate Hydride Transfer in Dihydrofolate ReductaseJournal of the American Chemical Society, 2005
- On Possible Pitfalls in ab Initio Quantum Mechanics/Molecular Mechanics Minimization Approaches for Studies of Enzymatic ReactionsThe Journal of Physical Chemistry B, 2005
- Improved pseudobonds for combined ab initio quantum mechanical/molecular mechanical methodsThe Journal of Chemical Physics, 2004
- Electrostatic Interactions Dominate the Catalytic Contribution of Arg39 in 4-Oxalocrotonate TautomeraseJournal of the American Chemical Society, 2004
- Computer Simulations of Enzyme Catalysis: Methods, Progress, and InsightsAnnual Review of Biophysics and Biophysical Chemistry, 2003
- Erratum: corrigendum: Contemporary fisherian life-history evolution in small salmonid populationsNature, 2003
- Structure and Catalytic Mechanism of a SET Domain Protein MethyltransferaseCell, 2002
- The language of covalent histone modificationsNature, 2000
- Comparison of simple potential functions for simulating liquid waterThe Journal of Chemical Physics, 1983
- Theoretical studies of enzymic reactions: Dielectric, electrostatic and steric stabilization of the carbonium ion in the reaction of lysozymeJournal of Molecular Biology, 1976