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Theoretical study of the H5N1 influenza virus enzyme catalyzes the hydrolysis of RNA reaction mechanism

Author: MaZuo
Tutor: ZhangYue
School: Shaanxi Normal University
Course: Physical and chemical
Keywords: H5N1 RNA endonuclease Catalyzed hydrolysis reaction mechanism Nucleophilic attack Density functional theory
CLC: O643.12
Type: Master's thesis
Year: 2011
Downloads: 35
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Abstract


The H5N1 virus is a highly pathogenic avian influenza virus has spread, mortality and high human infection has been formed to human health on a global scale of the threat. Polymerase has played an important role in the propagation of virus. Polymerase complex to capture the host cell mRNA, endonuclease of influenza virus polymerase to be used for the transcription of the viral mRNA. The If the endo active missing, virus can not be transcribed in the cell mRNA, thereby preventing the propagation of the virus. Therefore, the study of influenza virus polymerase enzyme to cleave RNA catalytic reaction mechanism, from the microscopic point of guidance related to drug development, has a very important theoretical and practical significance. In this thesis, density functional theory and Hartree-Fock method use GaussianO3 program cut within the PAN subunit of the H5N1 virus polymerase enzyme catalyzes the hydrolysis of RNA chain reaction mechanism was studied. In this thesis, the study includes screening methodology and study the reaction mechanism. Calculated during the reaction energy information of the various reactants, products, intermediates and transition states geometries, frequency and zero-point energy correction. The main contents and conclusions are summarized as follows: The first chapter describes the role of the hazards of the H5N1 virus and its endonuclease virus reproduction in the human body and the possible mechanism. In experiments on the use of X-ray measured endonuclease crystal data, and thereby infer the possible reaction mechanism of a single metal. The second chapter introduces the B3LYP used in this article, the HF method and basis set theoretical basis; looking for the transition state theory and method; used to calculate the biological system QM / MM method. Chapter III, In the X-ray crystal structure of (PDB: 3HW3), based on the magnesium ions as the center, and to select the active center 84 atoms as a model. The use of different methods of calculation model to optimize the optimized model and crystal data filter out the highest precision accuracy the best of the best optimization method - HF method. Each method based on the hydrogen atoms and heavy atoms plus diffuse functions, plus diffuse functions did not significantly improve the accuracy of the calculation, but lead to lower computational efficiency. Chapter IV, this article is designed according to the X-ray crystal structure (the PDB: 3EBJ and 3HW3) model A and model B containing a single metal ion. Model A contains a simple RNA chain, a catalytic effect of magnesium ion, the five amino acid residues and the three crystal water molecules. Model B one more than the Model A coordinated water molecules. Based on these two models to explore three possible reaction pathways. Each reaction pathways are included three key steps: (1) the transfer of a proton on the water molecules to the phosphate diester atom O (2), and OH-as a nucleophile to attack the P atom on the phosphate diester. (2) proton atom O (2) to go to one side of the atom O (1). (3) the proton atom O (2) transferred to the atom O (1) while the PO (1) bond rupture, 3 'hydroxyl group to leave. Looking for the various reactants, intermediates, transition states and products, HF/6-31G (d, p) method to optimize and calculate the frequency to determine the result of the stable configurations. B3LYP/6-31G (d, p) method to calculate the single-point energy compared by analyzing the potential energy surface, to determine the optimum reaction path. The results showed that the reaction energy barrier lowest divalent magnesium ions in the water molecule proton transfer process has played an important catalytic sources as the nucleophile with the the magnesium ligand of water molecules. The preferred reaction pathway (R1-TS11-INT11-TS21-INT21-TS31-P1), the relative energy of the reactants 0,110.40,91.58,143.02,102.04.110.82-12.96 kJ.mol-1. Calculations show that the three reaction pathway reaction -12.96, -59.80, 30.95kJ.mol-fifth chapter, the use of QM / MM method ONIOM (HF: UFF) level to optimize the H5N1 virus endonuclease during the catalyzed hydrolysis of RNA chain and the end of the two configurations, and calculate the frequency of the vibration, and IR spectra.

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CLC: > Mathematical sciences and chemical > Chemistry > Physical Chemistry ( theoretical chemistry ),chemical physics > Chemical kinetics,catalysis > Chemical kinetics > The mechanism and kinetics of chemical reactions
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