Theoretical Studies On Structure Prediction And Docking For Several Proteins

The complex structure of protein and its ligand is important forclarifying the function and action mechanisms of protein and it is useful fordrug design.To date,X-ray diffraction or NMR techniques have been themost valuable tools for elucidating structure-function relationships ofbiological molecules.Although the application of these experimentalmethods is continually growing,they remain time-consuming and limitedapplicability due to difficulties of accurate experimental data. With the rapiddevelopment of computer technology, computer aided molecular modelinghas become a very important and active research field in chemistry,biochemistry and molecular biology. In this dissertation, moleculardynamics simulations, quantum mechanical ab initio calculation methodsare used to build three dimension models of four proteins and study theirstructure properties in detail. Some creative results were obtained from themethods mentioned above. The main results are outlined as following:1. Homology modeling and docking studies for hepatitis B surface antigen fragmentHepatitis B virus (HBV) of man is the prototype member of the familyof hepatiae and concerns a major public health problem throughout theworld. The immune response HBV-encoded antigens are responsible bothfor viral clearance and for disease pathogenesis during this infection. By means of the homology modeling and docking methods, atheoretical study for hepatitis B surface antigen (HBsAg) fragment (44-170)is performed. The three-dimension structure of HBsAg fragment (44-170) isbuilt based on the crystal structures of whey acidic protein (PDB code 1CJH)and ricin glycosidase (PDB code 2AAI). A new ligand is designed based onthe structure of acceptor HBsAg (44-170) and the ligand is docking toHBsAg fragment. The result shows that Trp163 and Trp165 in the complexhave strong van der Waals contacts with the ligand, and this result is inagreement with the experimental one obtained by Wang et al. The hydrogenbonding interactions between ligand and tryptophan residues as well asproline residue of HBsAg also play an important role in locating effects. Ourresults may be helpful for further studies of the structure-based liganddesigning of new compounds.2. Molecular simulation studies of a selenium-containing scFv catalytic antibody that mimics glutathione peroxidase Glutathione peroxidase (GPx) is a mammalian antioxidant selenoenzymewhich protects biomembranes and other cellular components from oxidativedamage by catalyzing the reduction of a variety of hydroperoxides (ROOH),using glutathione (GSH) as the reducing substrate. The single-chain Fvfragment of the monoclonal antibody 2F3 (scFv2F3) can be converted intothe selenium-containing Se-scFv2F3 by chemical modification of the serine.The new selenium-containing catalytic antibody Se-scFv2F3 acts as a GPxmimic with high catalytic efficiency. In order to investigate which residue of scFv2F3 is converted intoselenocysteine and how to describe the proper reaction site of GSH toSe-scFv2F3, a three-dimensional structure of scFv2F3 is built by means ofhomology modeling. The 3D model is assessed by molecular dynamicssimulation to determine its stability and by comparison with those of knownprotein structures. After the serine in the scFv2F3 is modified toselenocysteine, a catalytic antibody (abzyme) is obtained. From geometricalconsiderations, the solvent-accessible surface of the protein is examined.The computer-aided docking and energy minimization calculations of theabzyme-GSH complex are then carried out to explore the possible active siteof the glutathione peroxidase mimic Se-scFv2F3. The structural informationfrom the theoretically modeled complex can help us to further understandthe catalytic mechanism of GPx.3. Homology modeling of dehalogenase and SN2 displacement reaction of fluoroacetate dehalogenase Various halogenated compounds have been synthesized and widely used as herbicides, insecticides, plastics and solvents, but many of them are toxic and cause serious environmental pollution. Microbial dehalogenases detoxify harmful halogenated compounds by cleaving their carbon–halogen bonds. Fluoroacetate dehalogenase (EC 3.8.1.3) catalyzes the dehalogenationof fluoroacetate and other haloacetates. In order to investigate the relationbetween the structure and the function, and understand the reactionmechanism of the enzyme, a 3D model of fluoroacetate dehalogenaseFAc-DEX FA1 is built by homology-based modeling. The 3D model isoptimized by unconstrained molecular dynamics simulation. Furthermore,the optimized 3D model was assessed by comparison of specific propertieswith two known protein structures. From the final 3D model, we find thatthe main residues involved in the active site in FAc-DEX FA1 are Phe34,Trp148, Tyr147, Tyr212, Asp104, and His271; especially Asp 104 is the keynucleophilic residue in substrate binding. A reaction model including Asp104 and the substrate fluoroacetate is then constructed and used tocharacterize explicit enzymatic reactions. In order to further illustrate...