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Technical aspects of quantum chemical modeling of enzymatic reactions: the case of phosphotriesterase
KTH, School of Biotechnology (BIO), Theoretical Chemistry.
Beijing Normal Univ, Coll Chem.
KTH, School of Biotechnology (BIO), Theoretical Chemistry.
2008 (English)In: Theoretical Chemistry accounts, ISSN 1432-881X, E-ISSN 1432-2234, Vol. 120, no 4-6, 515-522 p.Article in journal (Refereed) Published
Abstract [en]

Quantum chemical methods are today a powerful tool in the study of enzymatic reaction mechanisms. In this paper we evaluate the adequacy of some of the technical approximations frequently used in the modeling of enzyme reactions with high level methods. These include the choice of basis set for geometry optimizations and energy evaluation, the choice of dielectric constant to model the enzyme surrounding, and the effects of locking the centers of truncation. As a test case, we choose the phosphotriesterase enzyme, which is a binuclear zinc enzyme that catalyzes the hydrolysis of organophosphate triesters.

Place, publisher, year, edition, pages
2008. Vol. 120, no 4-6, 515-522 p.
Keyword [en]
SOLUBLE EPOXIDE HYDROLASE; REACTION-MECHANISM; BACTERIAL PHOSPHOTRIESTERASE; RIBONUCLEOTIDE REDUCTASE; PSEUDOMONAS-DIMINUTA; METHYL TRANSFER; WARFARE AGENTS; ACTIVE-SITE; DENSITY; ENZYMES
National Category
Chemical Sciences
Identifiers
URN: urn:nbn:se:kth:diva-9748DOI: 10.1007/s00214-008-0430-yISI: 000256765900022Scopus ID: 2-s2.0-45449084623OAI: oai:DiVA.org:kth-9748DiVA: diva2:127409
Note
QC 20100714Available from: 2008-12-05 Created: 2008-12-05 Last updated: 2010-07-14Bibliographically approved
In thesis
1. Quantum Chemical Modeling of Binuclear Zinc Enzymes
Open this publication in new window or tab >>Quantum Chemical Modeling of Binuclear Zinc Enzymes
2008 (English)Doctoral thesis, comprehensive summary (Other scientific)
Abstract [en]

In the present thesis, the reaction mechanisms of several di-zinc hydrolases have been explored using quantum chemical modeling of the enzyme active sites. The studied enzymes are phosphotriesterase (PTE), aminopeptidase from Aeromonas proteolytica (AAP), glyoxalase II (GlxII), and alkaline phosphatase (AP). All of them contain a binuclear divalent zinc core in the active site. The density functional theory (DFT) method B3LYP functional was employed in the investigations. The potential energy surfaces (PESs) for various reaction pathways have been mapped and the involved transition states and intermediates have been characterized. The hydrolyses of different types of substrates were examined, including phosphate esters (PTE and AP) and the substrates containing carbonyl group (AAP and GlxII). The roles of zinc ions and individual active-site residues were analyzed and general features of di-zinc enzymes have been characterized.

The bridging hydroxide stabilized by two zinc ions has been confirmed to be capable of the nucleophile in the hydrolysis reactions. PTE, AAP, and GlxII all employ the bridging hydroxide as the direct nucleophile. Furthermore, it is shown that either one of or both zinc ions provide the main catalytic power by stabilizing the negative charge developing during the reaction and thereby lowering the barriers. In the cases of GlxII and AP, one of zinc ions also contributes to the catalysis by stabilizing the leaving group. These features perfectly satisfy the two requisites for the hydrolysis, i.e. sufficient nucleophilicity and stabilization of charge. A competing mechanism, in which the bridging hydroxide acts as a base, was shown to have significantly higher barrier in the case of PTE.

For phosphate hydrolysis reactions, it is important to characterize the nature of the transition states involved in the reactions. Associative mechanisms were observed for both PTE and AP. The former uses a step-wise associative pathway via a penta-coordinated intermediate, while the latter proceeds through a concerted associative path via penta-coordinated transition states.

Finally, with PTE as a test case, systematic evaluation of the computational performance of the quantum chemical modeling approach has been performed. This assessment, coupled with other results of this thesis, provide an effective demonstration of the usefulness and powerfulness of quantum chemical active-site modeling in the exploration of enzyme reaction mechanisms and in the characterization of the transition states involved.

Place, publisher, year, edition, pages
Stockholm: KTH, 2008. viii, 66 p.
Series
Trita-BIO-Report, ISSN 1654-2312 ; 2008:27
Keyword
Quantum Chemical Modeling, Binuclear, Zinc, Enzyme, DFT, Mechanism
National Category
Theoretical Chemistry
Identifiers
urn:nbn:se:kth:diva-9705 (URN)978-91-7415-173-2 (ISBN)
Public defence
2008-12-19, FB53, AlbaNova, Roslagstullsbacken 21, Stockholm, 14:00 (English)
Opponent
Supervisors
Projects
Quantum Chemical Modeling of Binuclear Zinc Enzymes
Note
QC 20100715Available from: 2008-12-05 Created: 2008-11-28 Last updated: 2010-07-15Bibliographically approved

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