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The Beauty of the Bitter Devils: A Theoretical Study on Phosphate Molecules
Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics. (Andreas Barth)
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: urn:nbn:se:su:diva-65090ISBN: 978-91-86071-80-6 (print)OAI: oai:DiVA.org:su-65090DiVA: diva2:460894
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
List of papers
1. The Infrared Spectrum of Phosphoenol Pyruvate: Computational and Experimental Studies
Open this publication in new window or tab >>The Infrared Spectrum of Phosphoenol Pyruvate: Computational and Experimental Studies
Show others...
2009 (English)In: Journal of Physical Chemistry A, ISSN 1089-5639, E-ISSN 1520-5215, Vol. 113, no 12, 2935-2942 p.Article in journal (Refereed) Published
Abstract [en]

The infrared spectrum of phosphoenol pyruvate (PEP) in aqueous solution was studied experimentally and theoretically in its fully ionized, singly protonated and doubly protonated form. The density functional theory with the B3LYP functional and with the 6-31G(d,p), 6-31++G(d,p), and 6-311++G(d,p) basis sets were used in the theoretical study. The calculations with the two latter basis sets and the CPCM continuum model for water showed good agreement with the experiments except for vibrations assigned to hydroxyl groups. These needed to be modeled with explicit water molecules. The effects of deuteration and of 13C2,3 labeling of PEP were reproduced by the calculations.

National Category
Biochemistry and Molecular Biology
Research subject
Biophysics
Identifiers
urn:nbn:se:su:diva-32151 (URN)10.1021/jp809638u (DOI)000264348800033 ()
Available from: 2009-12-04 Created: 2009-12-04 Last updated: 2017-12-12Bibliographically approved
2. Basis Set Dependence of Phosphate Frequencies in Density Functional Theory Calculations
Open this publication in new window or tab >>Basis Set Dependence of Phosphate Frequencies in Density Functional Theory Calculations
2012 (English)In: International Journal of Quantum Chemistry, ISSN 0020-7608, E-ISSN 1097-461X, Vol. 112, no 11, 2435-2439 p.Article in journal (Refereed) Published
Abstract [en]

The addition of extravalence, polarization and diffuse functions, were studied in order to conclude how they affect the PO stretching frequencies of several biological relevant phosphate molecules. The results show that the polarization and the diffuse functions have opposite effects on the frequencies: the polarization functions downshift while the diffuse functions upshift the frequencies. The effect of the valence functions was more difficult to interpret. The effect of the conductor-like screening model (CPCM)-continuum model was also studied. The results show that the CPCM-continuum model has a substantial effect on the frequencies for these small molecules. The continuum model's efficiency is mainly due to its effect on the geometries and not on the frequencies.

Keyword
phosphate, frequencies, B3LYP, basis set, DFT
National Category
Theoretical Chemistry
Research subject
Biophysics
Identifiers
urn:nbn:se:su:diva-65012 (URN)10.1002/qua.23182 (DOI)000303198100012 ()
Available from: 2011-12-01 Created: 2011-11-30 Last updated: 2017-12-08Bibliographically approved
3. The influence of the molecular environment on phosphorylated amino acid models: A density functional theory study
Open this publication in new window or tab >>The influence of the molecular environment on phosphorylated amino acid models: A density functional theory study
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

National Category
Theoretical Chemistry
Research subject
Biophysics
Identifiers
urn:nbn:se:su:diva-65087 (URN)10.1021/jp206414d (DOI)000301169300013 ()
Note

3

Available from: 2011-12-01 Created: 2011-12-01 Last updated: 2017-12-08Bibliographically approved
4. Infrared Spectrum of E2P of Ca2+-ATPase
Open this publication in new window or tab >>Infrared Spectrum of E2P of Ca2+-ATPase
(English)Manuscript (preprint) (Other academic)
National Category
Theoretical Chemistry
Research subject
Biophysics
Identifiers
urn:nbn:se:su:diva-65088 (URN)
Available from: 2011-12-01 Created: 2011-12-01 Last updated: 2011-12-02Bibliographically approved
5. The hydrolysis of E2P of Ca2+-ATPase: A theoretical study
Open this publication in new window or tab >>The hydrolysis of E2P of Ca2+-ATPase: A theoretical study
(English)Manuscript (preprint) (Other academic)
National Category
Theoretical Chemistry
Research subject
Biophysics
Identifiers
urn:nbn:se:su:diva-65089 (URN)
Available from: 2011-12-01 Created: 2011-12-01 Last updated: 2011-12-02Bibliographically approved

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