Study On Interactions And Recognition Between Ligand And Protein

Recently, much attention has been paid to studying of interactions and recognition of bio-molecules by computer simulation approach. Molecule docking is one of the important simulation approaches and has many applications. The so-called molecule docking is to examine whether the two molecules can bind and predict the binding mode based on the three-dimensional structures of molecules. From the view of thermodynamics, native complex is the structure with the lowest binding free energy. Therefore, the aim of docking is to find the conformation with the lowest binding free energy.There are two important factors in the docking problem. One is an efficient search algorithm, which can explore the relevant conformational space, and the other is a good scoring function, which should be both reliable and efficient to discriminate between native and non-native solutions within a reasonable time.The main concept of this work includes the following aspects:(1) Based on the soft-docking algorithm which is improved upon Wodak and Janin's protein-protein rigid docking algorithm, we took seventeen protein-protein complexes for examples to study the method how to select the near-native structure from docking conformations. In this method, we compared the effect on discriminating near-native structures of different scoring functions, energy minimization (EM) and molecule dynamics (MD). 1) In filtering stage, a triple-filtering technique was implemented to select the reasonable binding modes. Subsequently, scoring and ranking were applied to the retained structures with several different combinations of the electrostatic, desolvation and van der Waals energy. In results, we found that the combined free-energy function containing thethree terms mentioned above has much more advantages on distinguishing the near-native structures from non-native ones. In addition, the results showed that EM is conducive to the scoring function to select the near-native structures with a smaller RMSD. 2) It is found that MD simulation can be used to further determinate the near-native structure. Taking two protein complexes, we performed MD simulations on their candidate structures. According to the variations of the mean square deviation (MSD) of the structures in MD trajectories relative to the initial structures, the false structures can be excluded.(2) In order to achieve the binding mode, the docking simulations were performed between glutathione (GSH) and different isomers of 99mTc-HMPAO with the package of AutoDock. The mechanism of the two molecules recognition and the effect of the stereoisomers on its retention in the brain in terms of the level of molecular and theoretical calculations were also discussed in our work.