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Exploring Protein Functions by Molecular Modelling
Stockholm University, Faculty of Science, Department of Materials and Environmental Chemistry (MMK).
2015 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Proteins are one of the most important families of biological macromolecules. Proteins can assume many different structures. This makes them perfect to serve a wide range of functions in all organisms. In the last decades, molecular modeling has become an important and powerful tool in the investigation of biological systems. Adopting different computational methods many protein functions and structure related problems can be explored.

This thesis focuses on three different protein issues. The structural changes induced by high temperature on a large enzyme were investigated simulating the denaturation of glucose oxidase. Molecular dynamics (MD) simulations at different high temperatures were performed. The transition state of the denaturation process was found and the relative ensemble of structures characterized. Different protein properties were analyzed and found in agreement with experimental and theoretical data. Moreover the breaking points of the protein were localized and point mutations on the protein sequence were suggested.

Antifreeze proteins (AFP) allow different organisms to survive in subzero environments. These proteins lower the freezing point of physiological fluids. MD simulations of the snow flea AFP (sfAFP) in water have shown partial instability of the protein structure. When attached to different ice planes at the ice/water interface, the sfAFP induces local ice melting. AFPs are divided into two categories: hyperactive and moderately active depending on their antifreeze power. The water diffusion profile of ice/water systems containing one protein from each family were compared. The ice/water interface width was found to be broadened to different extent by the two proteins, while a control protein (ubiquitin) did not affect the interface thickness.

Hemoglobin is the oxygen carrier in all vertebrates. Mutation along the protein sequence can alter the protein functionality and its capability of binding molecular oxygen. Density Functional Theory methods were applied in the calculation of the oxygen binding energy of the wild type hemoglobin and four other variants. Evaluations on the electronic structures and on the binding energies of the different hemoglobin variants suggest that perhaps none of the mutated hemoglibins efficiently bind oxygen.

Place, publisher, year, edition, pages
Stockholm: Department of Materials and Environmental Chemistry, Stockholm University , 2015. , 90 p.
National Category
Theoretical Chemistry
Research subject
Physical Chemistry
Identifiers
URN: urn:nbn:se:su:diva-114401ISBN: 978-91-7649-119-5 (print)OAI: oai:DiVA.org:su-114401DiVA: diva2:792136
Public defence
2015-04-17, Magnélisalen, Kemiska övningslaboratoriet, Svante Arrhenius väg 16 B, Stockholm, 10:00 (English)
Opponent
Supervisors
Note

At the time of the doctoral defense, the following paper was unpublished and had a status as follows: Paper 4: Manuscript.

Available from: 2015-03-26 Created: 2015-03-03 Last updated: 2015-03-27Bibliographically approved
List of papers
1. Glucose oxidase from Penicillium amagasakiense: Characterization of the transition state of its denaturation from molecular dynamics simulations
Open this publication in new window or tab >>Glucose oxidase from Penicillium amagasakiense: Characterization of the transition state of its denaturation from molecular dynamics simulations
2014 (English)In: Proteins: Structure, Function, and Genetics, ISSN 0887-3585, E-ISSN 1097-0134, Vol. 82, no 10, 2353-2363 p.Article in journal (Refereed) Published
Abstract [en]

Glucose oxidase (GOx) is a flavoenzyme having applications in food and medical industries. However, GOx, as many other enzymes when extracted from the cells, has relatively short operational lifetimes. Several recent studies (both experimental and theoretical), carried out on small proteins (or small fractions of large proteins), show that a detailed knowledge of how the breakdown process starts and proceeds on molecular level could be of significant help to artificially improve the stability of fragile proteins. We have performed extended molecular dynamics (MD) simulations to study the denaturation of GOx (a protein dimer containing nearly 1200 amino acids) to identify weak points in its structure and in this way gather information to later make it more stable, for example, by mutations. A denaturation of a protein can be simulated by increasing the temperature far above physiological temperature. We have performed a series of MD simulations at different temperatures (300, 400, 500, and 600 K). The exit from the protein's native state has been successfully identified with the clustering method and supported by other methods used to analyze the simulation data. A common set of amino acids is regularly found to initiate the denaturation, suggesting a moiety where the enzyme could be strengthened by a suitable amino acid based modification.

Keyword
protein denaturation, mutation, unfolding, MD simulation, cluster analysis
National Category
Biochemistry and Molecular Biology Biophysics Chemical Sciences
Research subject
Physical Chemistry
Identifiers
urn:nbn:se:su:diva-109018 (URN)10.1002/prot.24596 (DOI)000342849400006 ()
Note

AuthorCount:4;

Available from: 2015-01-09 Created: 2014-11-10 Last updated: 2017-12-05Bibliographically approved
2. Induced Ice Melting by the Snow Flea Antifreeze Protein from Molecular Dynamics Simulations
Open this publication in new window or tab >>Induced Ice Melting by the Snow Flea Antifreeze Protein from Molecular Dynamics Simulations
2014 (English)In: Journal of Physical Chemistry B, ISSN 1520-6106, E-ISSN 1520-5207, Vol. 118, no 47, 13527-13534 p.Article in journal (Refereed) Published
Abstract [en]

Antifreeze proteins (AFP) allow different life forms, insects as well as fish and plants, to survive in subzero environments. AFPs prevent freezing of the physiological fluids. We have studied, through molecular dynamics simulations, the behavior of the small isoform of the AFP found in the snow flea (sfAFP), both in water and at the ice/water interface, of four different ice planes. In water at room temperature, the structure of the sfAFP is found to be slightly unstable. The loop between two polyproline II helices has large fluctuations as well as the C-terminus. Torsional angle analyses show a decrease of the polyproline II helix area in the Ramachandran plots. The protein structure instability, in any case, should not affect its antifreeze activity. At the ice/water interface the sfAFP triggers local melting of the ice surface. Bipyramidal, secondary prism, and prism ice planes melt in the presence of AFP at temperatures below the melting point of ice. Only the basal plane is found to be stable at the same temperatures, indicating an adsorption of the sfAFP on this ice plane as confirmed by experimental evidence.

National Category
Chemical Sciences
Research subject
Physical Chemistry
Identifiers
urn:nbn:se:su:diva-111911 (URN)10.1021/jp508992e (DOI)000345722900027 ()
Note

AuthorCount:4;

Available from: 2015-01-12 Created: 2015-01-08 Last updated: 2017-12-05Bibliographically approved
3. Influence of Antifreeze Protein on the Ice/Water Interface
Open this publication in new window or tab >>Influence of Antifreeze Protein on the Ice/Water Interface
2015 (English)In: Journal of Physical Chemistry B, ISSN 1520-6106, E-ISSN 1520-5207, Vol. 119, no 8, 3407-3413 p.Article in journal (Refereed) Published
Abstract [en]

Antifreeze proteins (AFP) are responsible for the survival of several species, ranging from bacteria to fish, that encounter subzero temperatures in their living environment. AFPs have been divided into two main families, moderately and hyperactive, depending on their thermal hysteresis activity. We have studied one protein from both families, the AFP from the snow flea (sfAFP) and from the winter flounder (wfAFP), which belong to the hyperactive and moderately active family, respectively. On the basis of molecular dynamics simulations, we have estimated the thickness of the water/ice interface for systems both with and without the AFPs attached onto the ice surface. The calculation of the diffusion profiles along the simulation box allowed us to measure the interface width for different ice planes. The obtained widths clearly show a different influence of the two AFPs on the ice/water interface. The different impact of the AFPs here studied on the interface thickness can be related to two AFPs properties: the protein hydrophobic surface and the number of hydrogen bonds that the two AFPs faces form with water molecules.

National Category
Theoretical Chemistry
Research subject
Physical Chemistry
Identifiers
urn:nbn:se:su:diva-114443 (URN)10.1021/jp5119713 (DOI)000350329000008 ()
Available from: 2015-03-04 Created: 2015-03-04 Last updated: 2017-12-04Bibliographically approved
4. The Influence of Mutations at the Proximal Histidine Position on the Fe-O2 Bond in Hemoglobin from Density Functional Theory
Open this publication in new window or tab >>The Influence of Mutations at the Proximal Histidine Position on the Fe-O2 Bond in Hemoglobin from Density Functional Theory
(English)Manuscript (preprint) (Other academic)
National Category
Theoretical Chemistry
Research subject
Physical Chemistry
Identifiers
urn:nbn:se:su:diva-114786 (URN)
Available from: 2015-03-10 Created: 2015-03-10 Last updated: 2016-01-29Bibliographically approved

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