The Interactions, Structure Prediction And Free Energy Calculations Of Protein And Its Ligand

Molecular recognition is utilized to describe the molecular binding process in a specific manner. It's well known that the antibody/antigen, receptorAigand and enzyme/substrate are the three molecular recognition models in animate bodies. These binding and recognition are highly specific and usually act intelligently. Studies on these processes show great importance both in theory and application research aspects. It's always the focus of the international scientific research fields.Commonly, there are two kinds of methods to explore the molecular recognition, which is experimental method and computer simulation method. The latter plays a very important role in the study of the mechanism and dynamics of the recognition. It includes the molecular modeling, confirming the binding sites, the calculation of interactions between receptor and ligand, the docking research of the complex, the calculation of dynamic and thermodynamic properties etc. Many theoretical calculation methods are involved, such as quantum chemistry, molecular mechanisms, molecular dynamics, Monte Carlo method and Free Energy Calculation and so on. This work focuses on the Free Energy Calculation theory and its application, the docking research with empirical free energy calculation. It is mainly in the following three aspects.(1) A designed potential called "body restraint" or "molecular tweezers" were used to calculate the free energy contribution corresponding to the loss of translation and rotation freedom of the ligand molecule in binding procedure. This method was applied to calculate the absolute free energy of a benzamidine binding to a mutant trypsin D189G/G226D, which has the solvent accessible binding site. The calculationresult (-3.7 kcal ?mol-1) is satisfying with the experimental result (-2.5 kcal ?moP1).IV(2) The relative solvation free energies of "Tc brain imaging agents were calculated with the approach of thermodynamics integration and molecular transformation. The result indicates that the relative solvation free energy of these drugs could be used to estimate their brain uptakes and to predicate the influence of the site mutation of the complex on the brain uptakes. It is useful for new drug design.(3) The docking approach was applied to predicate the binding of HIV-1 integrase and its inhibitor aurintricaboxylic. The result indicates that the Mg2+ ion around the binding site is very important to stabilize the binding of the ligand to the receptor. The binding free energy estimated by the empirical function favors the system with one Mg2+ ion, in which the free energy is about 5 kcal/mol less than the system with Mg2+ ion.