Theortical study of free energy landscapes of biological macromolecules by the hybrid computation for electronic structure and molecular structure sampling

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1. Development of the hybrid-QM/MM calculation methodThe 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 proteinPin1 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 … More 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 hydrolysisTo 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