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Quantum Chemical Modeling of Enzymatic Methyl Transfer Reactions
KTH, School of Biotechnology (BIO), Theoretical Chemistry.
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 [en]
reaction mechanism
National Category
Theoretical Chemistry
Identifiers
URN: urn:nbn:se:kth:diva-9695ISBN: 978-91-7415-171-8 (print)OAI: oai:DiVA.org:kth-9695DiVA: diva2:127006
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
List of papers
1. Methyl transfer in glycine N-methyltransferase: a theoretical study
Open this publication in new window or tab >>Methyl transfer in glycine N-methyltransferase: a theoretical study
2005 (English)In: Journal of Physical Chemistry B, ISSN 1520-6106, E-ISSN 1520-5207, Vol. 109, no 16, 8216-8219 p.Article in journal (Refereed) Published
Abstract [en]

Density functional theory calculations using the hybrid functional B3LYP have been performed to study the methyl transfer step in glycine N-methyltransferase (GNMT). This enzyme catalyzes the S-adenosyl-l-methionine (SAM)-dependent methylation of glycine to form sarcosine. The starting point for the calculations is the recent X-ray crystal structure of GNMT complexed with SAM and acetate. Several quantum chemical models with different sizes, employing up to 98 atoms, were used. The calculations demonstrate that the suggested mechanism, where the methyl group is transferred in a single SN2 step, is thermodynamically plausible. By adding or eliminating various groups at the active site, it was furthermore demonstrated that hydrogen bonds to the amino group of the glycine substrate lower the reaction barrier, while hydrogen bonds to the carboxylate group raise the barrier.

Keyword
Carboxylation; Catalysis; Crystal structure; Functions; Molecular structure; Permittivity; X ray crystallography; Acetate molecules; Glycine; Methyl carbon; Methyl transfer
National Category
Theoretical Chemistry
Identifiers
urn:nbn:se:kth:diva-5570 (URN)10.1021/jp0443254 (DOI)000228603700084 ()2-s2.0-18444364203 (Scopus ID)
Note
QC 20100727Available from: 2008-12-04 Created: 2008-12-04 Last updated: 2017-11-21Bibliographically approved
2. Theoretical study of the methyl transfer in guanidinoacetate methyltransferase
Open this publication in new window or tab >>Theoretical study of the methyl transfer in guanidinoacetate methyltransferase
2006 (English)In: Journal of Physical Chemistry B, ISSN 1520-6106, E-ISSN 1520-5207, Vol. 110, no 1, 16-19 p.Article in journal (Refereed) Published
Abstract [en]

The reaction mechanism of the guanidinoacetate methyltransferase (GAMT) enzyme has been investigated by means of density functional theory using the B3LYP hybrid functional. GAMT catalyzes the S-adenosyl-l-methionine (SAM)-dependent methylation of guanidinoacetate (GAA) to form creatine. A quantum chemical model was built on the basis of the recent crystal structure of GAMT complexed with S-adenosylhomocysteine (SAH) and GAA. The methyl group transfer from SAM to NE of GAA is shown to occur concertedly with a proton transfer from NE to the neighboring OD1 of Asp134. Good agreement is found between the calculated barrier and the experimental rate.

Keyword
Catalysis; Crystal structure; Enzymes; Hybrid computers; Probability density function; Propylene; Structural analysis; Creatine; Guanidinoacetate methyltransferase; Methylation; S-adenosylhomocysteine (SAH)
National Category
Theoretical Chemistry
Identifiers
urn:nbn:se:kth:diva-5571 (URN)10.1021/jp055120d (DOI)000234520700006 ()
Note
QC 20100727Available from: 2008-12-04 Created: 2008-12-04 Last updated: 2017-11-21Bibliographically approved
3. The reaction mechanism of phenylethanolamine N-methyltransferase: A density functional theory study
Open this publication in new window or tab >>The reaction mechanism of phenylethanolamine N-methyltransferase: A density functional theory study
2009 (English)In: Biochimica et Biophysica Acta - Proteins and Proteomics, ISSN 1570-9639, E-ISSN 1878-1454, Vol. 1794, no 12, 1831-1837 p.Article in journal (Refereed) Published
Abstract [en]

Hybrid density functional theory methods were used to investigate the reaction mechanism of human phenylethanolamine N-methyltransferase (hPNMT). This enzyme catalyzes the S-adenosyl-L-methionine-dependent conversion of norepinephrine to epinephrine, which constitutes the terminal step in the catecholamine biosynthesis. Several models of the active site were constructed based on the X-ray structure. Geometries of the stationary points along the reaction path were optimized and the reaction barrier and energy were calculated and compared to the experimental values. The calculations demonstrate that the reaction takes place via an S(N)2 mechanism with methyl transfer being rate-limiting, a suggestion supported by mutagenesis studies. Optimal agreement with experimental data is reached using a model in which both active site glutamates; are protonated. Overall, the mechanism of hPNMT is more similar to those of catechol O-methyltransferase and glycine N-methyltransferase than to that of guanidinoacetate N-methyltransferase in which methyl transfer is coupled to proton transfer.

Keyword
Quantum chemistry, Enzyme mechanism, Methyl transfer, Mutagenesis, pK(a)
National Category
Theoretical Chemistry
Identifiers
urn:nbn:se:kth:diva-24818 (URN)10.1016/j.bbapap.2009.08.022 (DOI)000271293700013 ()2-s2.0-73049101676 (Scopus ID)
Note
QC 20100927. Uppdaterad från manuskript till artikel (20100927).Available from: 2010-09-27 Created: 2010-09-27 Last updated: 2017-12-12Bibliographically approved
4. Quantum Chemical Modeling of Enzymatic Reactions: The Case of Histone Lysine Methyltransferase
Open this publication in new window or tab >>Quantum Chemical Modeling of Enzymatic Reactions: The Case of Histone Lysine Methyltransferase
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.

Keyword
enzyme catalysis, density functional theory, methyltransferase
National Category
Theoretical Chemistry
Identifiers
urn:nbn:se:kth:diva-24819 (URN)10.1002/jcc.21458 (DOI)000277483500016 ()
Note
QC 20100927. Uppdaterad från manuskript till artikel (20100927).Available from: 2010-09-27 Created: 2010-09-27 Last updated: 2017-12-12Bibliographically approved
5. Density functional theory study of the reaction mechanism of the DNA repairing enzyme alkylguanine alkyltransferase
Open this publication in new window or tab >>Density functional theory study of the reaction mechanism of the DNA repairing enzyme alkylguanine alkyltransferase
2008 (English)In: Chemical Physics Letters, ISSN 0009-2614, E-ISSN 1873-4448, Vol. 463, no 1-3, 214-218 p.Article in journal (Refereed) Published
Abstract [en]

The reaction mechanism of human O6-alkylguanine-DNA alkyltransferase (AGT) is studied using density functional theory. AGT repairs alkylated DNA by directly removing the alkyl group from the O6 position of the guanine. A quantum chemical model of the active site was devised based on the recent crystal structure of the AGT–DNA complex. The potential energy curve is calculated and the stationary points are characterized. It is concluded that the previously proposed reaction mechanism is energetically plausible. In this mechanism, His146 first acts as a water-mediated general base to activate Cys145, which then performs a nucleophilic attack to dealkylate the guanine base.

Keyword
alkylguanine alkyltransferase
National Category
Theoretical Chemistry
Identifiers
urn:nbn:se:kth:diva-9699 (URN)10.1016/j.cplett.2008.08.043 (DOI)000259150400042 ()2-s2.0-51349146401 (Scopus ID)
Note
QC 20100727Available from: 2008-12-04 Created: 2008-11-27 Last updated: 2010-09-27Bibliographically approved

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