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The influence of the molecular environment on phosphorylated amino acid models: A density functional theory study
Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics.
Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics.
2012 (English)In: Journal of Physical Chemistry B, ISSN 1520-6106, E-ISSN 1520-5207, Vol. 116, no 9, 2751-2757 p.Article in journal (Refereed) Published
Abstract [en]

A protein environment can affect the structure and charge distribution of substrate molecules. Here, the structure and partial charges were studied for different phosphorylated amino acid models in varying environments using density functional theory. The three systems investigated, acetyl phosphate, methyl phosphate, and p-tolyl phosphate are representative models for aspartyl phosphate, serine or threonine phosphate, and tyrosine phosphate, respectively. Combined with the CPCM continuum model, explicit HF and H2O molecules were added in order to model environmental effects and interactions that may occur in a protein matrix. We show how the different interactions affect the scissile P–O(R) bond and that the elongation can be explained by an anomeric effect. An increasing scissile bond length will result in transfer of negative charge to the leaving group and in a widening of the angle between the terminal oxygens of the phosphate molecule, features that can expose the phosphate group to attacking nucleophiles. Lastly, calculations were performed on the active site of the Ca2+-ATPase E2P intermediate, which provide an example of how a protein environment facilitates the formation of a destabilized ground state

Place, publisher, year, edition, pages
2012. Vol. 116, no 9, 2751-2757 p.
National Category
Theoretical Chemistry
Research subject
Biophysics
Identifiers
URN: urn:nbn:se:su:diva-65087DOI: 10.1021/jp206414dISI: 000301169300013OAI: oai:DiVA.org:su-65087DiVA: diva2:460874
Note

3

Available from: 2011-12-01 Created: 2011-12-01 Last updated: 2017-12-08Bibliographically approved
In thesis
1. The Beauty of the Bitter Devils: A Theoretical Study on Phosphate Molecules
Open this publication in new window or tab >>The Beauty of the Bitter Devils: A Theoretical Study on Phosphate Molecules
2011 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Phosphate transfer reactions are catalyzed by a large number of enzymes comprising kinases, mutases and phosphatases. These enzymes play a fundamental role in controlling numerous life processes and it is therefore important to understand the origin of their potent catalytic power. An example is the Ca2+-ATPase. In the E2P-state, this enzyme hydrolyses the phosphorylated amino acid, Asp351, 106 to 107 fold faster than when the model compound, acetyl phosphate, is hydrolyzed in in water.This thesis explores the catalytic power of Ca2+-ATPase using theoretical method based on quantum mechanics. The studies of this protein were made by performing quantum chemical calculations on models of phosphoric monoesters as well as on the explicit reaction pathway of the hydrolysis. The studies show the importance of electrostatic interactions as well as the role of the specific active site residue Glu183, a residue that acts as a base in the catalytic pathway. Furthermore, based on the calculations, the interpretation of the experimental infrared spectrum of the E2P-state of Ca2+-ATPase, could be further elucidated as well as modified.The experimental infrared spectrum of phosphoenol pyruvate in water has also been elucidated through calculations. This molecule is converted into pyruvate in the last step of the glycolytic pathway, a reaction that is catalyzed by pyruvate kinase (PK). These results further enabled the interpretation of the experimental spectrum of the PK's catalytic reaction.These two processes, the transport of Ca2+ into the sarcoplasmatic reticulum against a concentration gradient and the glycolysis, are two important actions of a muscle cell.

Place, publisher, year, edition, pages
Stockholm: Department of Biochemistry and Biophysics, Stockholm University, 2011. 65 p.
National Category
Theoretical Chemistry
Research subject
Biophysics
Identifiers
urn:nbn:se:su:diva-65090 (URN)978-91-86071-80-6 (ISBN)
Public defence
2012-01-13, Magnélisalen, Kemiska övningslaboratoriet, Svante Arrhenius väg 16 B, Stockholm, 10:00 (English)
Opponent
Supervisors
Note
At the time of the doctoral defense, the following papers were unpublished and had a status as follows: Paper 2: Epub ahead of print. Paper 3: Submitted. Paper 4: Manuscript. Paper 5: Manuscript.Available from: 2011-12-15 Created: 2011-12-01 Last updated: 2011-12-20Bibliographically approved

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