Computer Simulation Of Binding Free Energy And Conformational Changes For Bio-Macromolecule

Molecular recognition is of central importance in biology and pharmacology. It underlies the action of hormones, the control of DNA transcription, the recognition of Antigens-Antibody in the immune system, the catalysis of chemical reactions by enzymes and the actions of many drugs. Calculations of absolute binding free energy play a very important role in the study of the mechanism and dynamics of the molecular recognition. The orientation of chemical reactions depends on the sign of binding free energy and the tendency depending on its corresponding value. Many groups have invested ingenuity and effort in the development of such models, double annihilation method developed by Jorgensen was proposed as a classical way of computing the absolute binding free energy of a complex in solution, which has been applied in a number of studies. In the first part of this thesis, The binding free energy between GlnBP monomer and its ligand Gin was computed by using the classical double annihilation method. It is found that the result (-14.59 kcal/mol) agrees well with experimental data (-8.025 kcal/mol). The advantage and disadvantage of this methods are analyzed.During the past several decades, molecular dynamics (MD) simulation of proteins has become a widely used tool to deepen our understanding of the molecules. Computer simulation techniques can be used to understand the properties of a molecular system in terms of interactions at the atomic level. The results of MD simulations are very useful to understand the relation between the macromolecularconformational changes and its biological function. In the second part of this thesis, we have chosen the protein monomer GlnBP and complex GlnBP-Gln as our study systems. The MD simulations were carried out with the GROMOS96 package and its force field for 600 ps. The MD simulation data were analyzed in terms of the overall structure, the binding free energy, the flexibility hi the region around hinges, the interactions in the binding site, pocket ligand binding specificity, and so on. The results obtained from the biochemistry experiment can be correctly identified by our MD simulations.The study on solvation effect is the focus of the international scientific research fields. The electrostatic interaction is the most important part hi the solvation effect, especially when the solute is charged or highly polarized. Commonly, the general Poisson-Boltzmannn (PB) equation can well describe the electrostatic property of a protein in solution. We use a finite difference method to solve PB equation and incorporate the solution into SD simulation, which is called as FDSD simulation procedure and developed by our group before. The solvent is considered as a continuum in FDSD simulation procedure, which gained success in simulation of smaller proteins. In the last part of this thesis, the R-state human insulin hexamer has been selected as a target. A comparison has been made among the results obtained with FDSD simulation, MD simulation and SD simulation. The results show that the FDSD simulation has obvious improvement over the SD simulation for structure and dynamics properties, and has a good agreement with that of the MD simulation.