Theortical study of free energy landscapes of biological macromolecules by the hybrid computation for electronic structure and molecular structure sampling
| Project/Area Number |
18370063
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| Research Category |
Grant-in-Aid for Scientific Research (B)
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| Allocation Type | Single-year Grants |
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| Section | 一般 |
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| Research Field |
Biophysics
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| Research Institution | Osaka University |
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Principal Investigator |
NAKAMURA Haruki Osaka University, Institute for Protein Research, Professor (80134485)
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| Co-Investigator(Kenkyū-buntansha) |
YONEZAWA Yasushige Osaka University, Institute hr Protein Research, Specially Appointed Researcher (40248753)
TAKANO Yu Osaka University, Institute for Protein Research, Assistant Professor (30403017)
OSHIMA Kanji Osaka Uniyersity, The Center for Adanced Medital Engineering and Informatics, Specially Appointed Assistant Professor (40437330)
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| Project Period (FY) |
2006 – 2007
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| Project Status |
Completed (Fiscal Year 2007)
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| Budget Amount *help |
¥5,420,000 (Direct Cost: ¥4,700,000、Indirect Cost: ¥720,000)
Fiscal Year 2007: ¥3,120,000 (Direct Cost: ¥2,400,000、Indirect Cost: ¥720,000)
Fiscal Year 2006: ¥2,300,000 (Direct Cost: ¥2,300,000)
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| Keywords | Biophysics / Enzymatic reaction / Biological macromolecules / Quantum chemistry / Molecular dynamics / Molecular simulation / Electron state / Reaction free energy |
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| Research Abstract |
1. Development of the hybrid-QM/MM calculation method
The hybrid-QM/MM method combines the advantages in the quantum chemistry and the molecular mechanics for the accurate simulation of a protein-solvent system, by treating the essential region of a protein by quantum mechanics and applying the classical Newtonian equations to the rest of the target system. We have developed a software program for the novel hybrid-QM/MM simulations.
2. The hybrid-QM/MM simulation study on the mechanism of proline cis-trans isomerization of human Pin 1 protein
Pin1 is one of human peptidyl-prolyl isomerases, which catalyzes the cis-trans isomerization of a proline residue. This enzyme is associated with a cancerous change of cells and apoptosis, and its close relationships with Alzheimer's disease has also been reported. We have studied the isomerization mechanism of this enzyme, by calculating the electronic structure of the peptide bond at the proline in the ligand and sampling the protein and the surrou
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nding solvent molecular structures. Finally, we have revealed the reaction and conformation free energy change including the entropy effect.
3. Molecular orbital and molecular dynamics studies of the reaction mechanism of the enzyme-catalyzed hydrolysis
To understand how the conformational factors are related to enzyme-catalyzed hydrolysis by lipases, conformational analysis was performed by molecular dynamics simulations for the tetrahedral intermediates bound to lipases. Consequently, we found the similar conformational preference to the intermediates of the transacylation of methyl acetate computed by molecular orbital theory. In molecular dynamics simulation for the two-metal mechanism of the RNase H catalysis, the distance between two Mg^<2+> ions in the active site drifted apart due to the electrostatic repulsion, resulting in the disruption of the active site. Density functional calculation shows that esters of cyclopropanecarboxylic acid demonstrate a substantial increase in stability under base-catalyzed hydrolysis compared to other esters. Less
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Report
(3 results)
Research Products
(108 results)
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[Journal Article] Cyclopropanecarboxylic Acid Esters as Porential Prodrugs with Enhanced Hydrolytic Stability2008
Author(s)
D. M., Bender, J. A., Peterson, J. R., McCarthy, H., Gunaydin, Y., Takano, K. N., Houk
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Journal Title
Organic Letters 10 (3)
Pages: 509-511
Description
「研究成果報告書概要(欧文)」より
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[Journal Article] Application of MDGRAPE-3, a special purpose board for molecular dynamics simulations, to periodic biomolecular systems2008
Author(s)
G., Kikugawa, R., Apostolov, N., Kamiya, M., Taiji, R., Himeno, H., Nakamura, Y., Yonezawa
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Journal Title
Journal of Computational Chemistry 29 (in press)
Description
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[Journal Article] Utilization of methyl proton resonances in cross-saturation measurement for determining the interfaces of large protein-protein complexes2006
Author(s)
H., Takahashi, M., Miyazawa, Y., Ina, Y., Fukunishi, Y., MIzukoshi, H., Nakamura, I., Shimada
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Journal Title
Journal of Biomolecular NMR 34 (12)
Pages: 167-177
Description
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[Journal Article] Effect of Hunter Disease mutations on molecular phenotypes of iduronate-2-sulfonate : Enzymatic activity, protein processing and structural analysis2006
Author(s)
K., Sukegawa-Hayasaka, Z., Kato, H., Nakamura, S., Tomatsu, T., Fukao, K., Kawata, T., Orii, N., Kondo
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Journal Title
Journal of Inherited Metabolic Disease 29 (6)
Pages: 755-761
Description
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[Presentation] Folding simulation of a 40-residue protein, H-NS, involving alpha and beta secondary structures in explicit water2007
Author(s)
J., Higo, J., Ikebe, N., Kamiya, H., Nakamura, H., Shindo
Organizer
45'th Annual Meeting of Biophysical Society of Japan
Place of Presentation
Pacifico Yokohama, Yokohama
Year and Date
2007-12-22
Description
「研究成果報告書概要(欧文)」より
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[Presentation] Molecular simulations of protein-ligand structures constructed by computational doking2007
Author(s)
A., Oda, Y., Takano, H., Nakamura, N., Yamaotsu, S., Hirono, O., Takahashi, H., Matsuzaki
Organizer
45'th Annual Meeting of Biophysical Society of Japan
Place of Presentation
Pacifico Yokohama, Yokohama
Year and Date
2007-12-21
Description
「研究成果報告書概要(欧文)」より
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[Presentation] Computational studies of the substrate recognition mechanism of Escherichia coil endonuclease III2007
Author(s)
K., Manabe, Y., Takano, K., Hitomi, J.A., Tainer, H., Nakamura, N., Iwai
Organizer
BMB 2007
Place of Presentation
Pacifico Yokohama, Yokohama
Year and Date
2007-12-13
Description
「研究成果報告書概要(欧文)」より
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