Docking And Molecular Dynamics Simulation Based On 6-Hydroxymethyl-7,8-Dihydropterin Pyrophosphokinase

The thesis is about molecular docking and molecular dynamics simulation theoretical calculation on 6-hydroxymethyl-7,8-dihydropterin pyrophosphokinase (HPPK), complexs and mutates. In addition, some improvements have been done on the quantitive structure — activity/property relationshitp. There are the main parts:In the first part, molecular docking studies have been performed based on HPPK by using DOCK4.0 software. Firstly, two methods (Connolly and Dms) were used to creat the receptor surface, in the same time, different active site sizes were also considered to perform the docking calculation. We found that in the proper active site, the docking results calculated by Connolly were smoother than those got by Dms, and the complex structures were much closer to the X-ray structures. The rmsd values were closer to 2A, but the parameters were still not used for the database screening.Then, the Mg²⁺ cations were held in the active pocket. Molecular docking studies on the interactions of HPPK with the substrate analogures have been performed. Particularly, the effect of the intrinsic metal ion upon the docking has been examined. It has been showed that the incorporation of Mg²⁺ cation in the molecular docking processes plays an important role not only in obtaining reliable docking resules but also in improving the hit ratio in the "in silico" drug scrrening.Finally, the MDL/ACD3D database docking into HPPK were performed by using Connolly method and considering Mg²⁺ cations. Analyzing the docking results, we found that some compounds have inhibitor activity on HPPK on theoretical, whose similar structures were also found. The compounds should be done the pharmacological experimental to prove the activity. Thus, the docking study may provide some helpful information for our designing new antimicrobial agents based on HPPK.In the second part, the focus is the molecular dynamics simulation on HPPK, the complex and mutates. Firstly, moleclar dynamics calculations were performed on HPPK, which were in vacuo, water, and water adding the counter ions respectively. It shown that the molecular dynamics of HPPK in the water adding the counter ions was most close to the experiment from the trajectory of rmsd, radus of gyrate, the secondary structure, eigenvectors, and the Ca covariance matrix.Then, HP and ATP were docked into HPPK with or without two Mg-+ ions and three cooridnated water molecules, using the flexible dock program (FlexiDock). 2000 ps molecular dynamics simulations were carried out to refine the four docked complex systems. The simulation shows the stability and validity of the complex structure. Two Mg2+ ions are both octahedral coordination. One Mg2* ion is chelated with an oxygen atom of HP, which is favorable to the transfer of pyrophosphoryl from ATP to HP, and neutralizes the negative charge so as to stabilize the conformation of the comples (HPPK-HP-ATP). The three water molecules coordinate with two Mg2+ and other residues are also steady during molecular dynamics simulation, which are therefor termed "structural water" and contribute significantly to the stability of biomacromolecules and play a crucial role in molecular association.In order to.make clear the function of residue Arg82, Arg92, and 84-89 during HP and ATP binding to HPPK, molecular dynamics simulations were done on HPPK and mutates. We found that the residue Arg82, Arg92, and 84-89 are in the flexible Ioop2 and Ioop3. During the HP binding to HPPK process, the Ioop2 and Ioop3 have large conformational change and moved into the active site to bind with HP and ATP. In addition, mechanism of HPPK-catalyzed pyrophosphoryl transfer was devining qualitatively from the X-ray structure and models.In the last part, the quantitative structure — activity/property relationship models were built by using 2-dimensional and 3-dimensial methods. Ab initio HF/6-31G* optimization and electrostatic potentials have been computed for anumber of disubstituted benzenes. A good six-parameter correlation between logP and the computed descriptors for a training set of representative disubstituted benzenes is presented. The influence of group-group interactions on the logP values of isomers has been investigated by treating the ortho disubstituted benzenes separated from the others. It shows that the influences of interactions between two neighbouring substituent groups are basically thought to be relevant to hydrogen-bonding and represented mainly by variations of the Vmin, VS;max as well as PSA values of isomers.Ab initio optimization at HF/6-31G* level and electrostatic potential calculations have been performed for a group of 121 solvent molecules. High-level correlation of solubilities of fullerence (C6o) in organic solvents with the theoretical descriptors of solvents have been obtained. The results slso demonstrate that the solubilities of fullerence can be predicted better with the selective parameters, and the results obtained by neural network are superior to that by multiple regression.By using comparative molecular field analysis (CoMFA) method, quantitative structure-activity relationship modles have been built for the inhibitors of acethylcholinesterase and a series of phenoxyalkylamines ai-adrenoceptor antagonist (DDPH and its analogues), good models were obtained. The progresses (rotation and translation based on the conventional CoMFA (model) have improved the predicted power of the models.