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Quantum Chemical Modeling of Enzymatic Reactions: The Case of Histone Lysine Methyltransferase
Department of Organic Chemistry, Arrhenius Laboratory, Stockholm University.
Department of Organic Chemistry, Arrhenius Laboratory, Stockholm University.
2010 (English)In: Journal of Computational Chemistry, ISSN 0192-8651, E-ISSN 1096-987X, Vol. 31, no 8, 1707-1714 p.Article in journal (Refereed) Published
Abstract [en]

Quantum chemical cluster models of enzyme active sites are today an important and powerful tool in the study of various aspects of enzymatic reactivity. This methodology has been applied to a wide spectrum of reactions and many important mechanistic problems have been solved. Herein, we report a systematic study of the reaction mechanism of the histone lysine methyltransferase (HKMT) SET7/9 enzyme, which catalyzes the methylation of the N-terminal histone tail of the chromatin structure. In this study, HKMT SET7/9 serves as a representative case to examine the modeling approach for the important class of methyl transfer enzymes. Active site models of different sizes are used to evaluate the methodology. In particular, the dependence of the calculated energies on the model size, the influence of the dielectric medium, and the particular choice of the dielectric constant are discussed. In addition, we examine the validity of some technical aspects, such as geometry optimization in solvent or with a large basis set, and the use of different density functional methods.

Place, publisher, year, edition, pages
2010. Vol. 31, no 8, 1707-1714 p.
Keyword [en]
enzyme catalysis, density functional theory, methyltransferase
National Category
Theoretical Chemistry
Identifiers
URN: urn:nbn:se:kth:diva-24819DOI: 10.1002/jcc.21458ISI: 000277483500016OAI: oai:DiVA.org:kth-24819DiVA: diva2:353458
Note
QC 20100927. Uppdaterad från manuskript till artikel (20100927).Available from: 2010-09-27 Created: 2010-09-27 Last updated: 2017-12-12Bibliographically approved
In thesis
1. Quantum Chemical Modeling of Enzymatic Methyl Transfer Reactions
Open this publication in new window or tab >>Quantum Chemical Modeling of Enzymatic Methyl Transfer Reactions
2008 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

In this thesis, quantum chemistry, in particular the B3LYP density functional method, is used to investigate a number of methyl transfer enzymes. Quantum chemical methodology is today a very important tool in the elucidation of properties and reaction mechanisms of enzyme active sites. The enzymes considered in this thesis are the S-adenosyl L-methionine-dependent enzymes - glycine N-methyltransferase, guanidinoacetate methyltransferase, phenylethanolamine N-methyltransferase, and histone lysine methyltransferase. In addition, the reaction mechanism of the DNA repairing enzyme O6-methylguanine methyltransferase is studied. Active site models of varying sizes were designed and stationary points along the reaction paths were optimized and characterized. Potential energy surfaces for the reactions were calculated and the feasibility of the suggested reaction mechanisms was able to be judged. By systematically increasing the size of the models, deeper insight into the details of the reactions was obtained, the roles of the various active site residues could be analyzed, and, very importantly, the adopted modeling strategy was evaluated.

Place, publisher, year, edition, pages
Stockholm: KTH, 2008. ix, 51 p.
Series
Trita-BIO-Report, ISSN 1654-2312 ; 2008:26
Keyword
reaction mechanism
National Category
Theoretical Chemistry
Identifiers
urn:nbn:se:kth:diva-9695 (URN)978-91-7415-171-8 (ISBN)
Public defence
2008-12-18, FB53, AlbaNova, Roslagstullsbacken 21, Stockholm, 10:00 (English)
Opponent
Supervisors
Note
QC 20100927Available from: 2008-12-04 Created: 2008-11-27 Last updated: 2010-09-27Bibliographically approved

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