Theoretical Study Of The Molecular Functions Of Several Proteins

Since 1990s, with computer science rapidly developing, Bioinformatics has got a lot of progress. Protein plays an important role in study, whose structure simulation has been a field of research in Bioinformatics. Structure model of protein was built and structural features of protein were studied by means of molecular modeling methods and molecular dynamics methods. Moreover, the interaction model between the ligands and receptors in physical environment could be obtained. The biochemical mechanism and drug design has become an important tool in molecular biology and modern medical research.In this paper, by means of molecular mechanics method, molecular docking method and molecular dynamics methods, the interaction between protein molecule and DNA molecule, protein molecule and protein inhibitors were studied. Meanwhile, the mechanisms of the interaction between the ligands and receptors in the three systems of arginine arginase, LRH-1(human liver receptor homologue-1) and HIV-1 Vif protein not resolved in experiments were revealed in theory.1. Positioning of Ftz-F1 Domain affects on the activity of human LRH-1: molecular dynamics study on human LRH-1-DNA complexesThe human liver receptor homologue-1 (LRH-1; NR5A2) as an important member of the nuclear receptor (NR) super family of metazoan transcription factors regulates the expression of gene products central to embryonic development and adult homeostasis. Nuclear receptor DNA binding domain and ligand binding domain is generally considered to operate independently, and their connection is flexible to a certain extent. Isaac H. Solomon et al. recently have reported that Ftz-F1 domain positioning can affect the transcriptional activity of full-length hLRH-1 significantly. They found that disrupting the Ftz-F1 helix positioning by mutating some conserved residues in hLRH-1 does not eliminate DNA binding but reduces the transcriptional activity of hLRH-1, moreover, the activity could not be rescued by the addition of transcriptional coactivator GRIP1. These results suggest the positions of Ftz-F1 domain may directly affect the DNA recognition. However how does the Ftz-F1 regulate the transcriptional activity of hLRH-1 in details is unclear. In our study, we refer to these complexes as followed. The first system had the high activity hLRH-1 (95 amino acids residues) of NR family and 12 base pairs DNA of the response element from the human CYP7A1gene. The second system was low activity hLRH-1 involving double mutation (G169V/P170A), while the third system was meta-active state hLRH-1 involving triple mutant (Y96A/F168A/Y172/A). Here, we refer to these complexes as wild type, double-mutant and triple-mutant, respectively. We report 5ns MD simulations of three hLRH-1–DNA complex systems. The results indicate the stability at about 1.9ns in the wild form, whereas RMSD becomes stable after 1.5ns and 1.7ns in the double mutant and triple mutant forms. The formation of hydrogen bonds and the number of key bases in the long loop is the reason why the wild-type has relative high RMSD, compared to other two MD structures. Comparative analyses of the three MD trajectories of hLRH-1 complexes suggest that the differential transcriptional activities of the wild-type hLRH-1, double-mutant and triple-mutant are due to alterative protein-DNA interactions. As results, the relative motions between the FTz-F1 domain and the DBD in the hLRH-1 can change the distributions of the electrostatic potential surface in the entire DNA-binding region, and the changes of the electrostatic potential surface can directly affect the conformations of the bound DNA and further make an impact on the transcriptional activity in the three systems.2. Study on interaction between ArginaseⅠand ButylphthalideArginase is a metalloenzyme with two core containing manganese. There are two subtypes of Arginase found: ArginaseΙand ArginaseⅡ. They were more than 60% same in homology. The main differences lie in their tissue distribution, subcellular localization and immunoreactivity. ArginaseΙis mainly expressed in the cytoplasm of the liver, brain and other place, Arginine can be metabolized to ornithine and urea in presence of ArginaseΙ, which plays an important role in polyamines of ornithine metabolism. Based on earlier studies, it has been found that Arginase exists in the vascular system. When blood vessels were damaged, a large number of Arginase were expressed in vascular smooth cells. N-butylphthalide (NBP) is a single-lactone drug molecules extracted from Chinese Medicines, by metabolomics. Moreover, how does L- N-butylphthalide interact with ArginaseΙin details is unclear. In this study, the complexes of ArginaseΙand Chiral Butylphthalide (L- and D-) was investigated by means of molecular docking and molecular dynamics simulations. From these results as followed: the structures of two complexes become stable at 3.5ns, the interaction energy and the number of hydrogen bonds of D-arginine was smaller than those of L-arginine and the distance was more larger from guanidine in D-arginine to manganese ions, it was concluded that L-arginine was the substrate of ArginaseⅠ. Meanwhile, the interaction between ArginaseΙand N-butylphthalide (NBP) was also investigated in this study, it was found that the structures become stable at 1ns, and D-NBP moved to the edge of the active pocket of ArginaseⅠat 1100-1300ps, so the complex of D-NBP and ArginaseⅠwas less stable than the complex of L-NBP and ArginaseⅠ. In summary, it was confirmed that the L-NBP has the obvious activation function to the ArginaseΙ, but the D- NBP does not have the obvious influence to the ArginaseΙ. These conclusions provided a theoretical basis for drug design.3.Molecular dynamics simulation of the action mode between a long peptide inhibitor and the Vif-Elongin C proteinHIV-1 Vif protein was one of the six accessory proteins encoded by Virus, which was widely present in all lentivirus belonging to retroviral division. HIV-1 Vif protein interacts with the antiviral factor APOBEC3G (A3G) in vivo, which is a cytosine amino acid enzyme with natural anti-viral activity. A3G can mutate guanine purine base to adenine base in HIV-1 genome, which inhibits HIV-1 replication. However, its anti-virus function can be antagonized by HIV-1 Vif protein. It was due to that HIV-1 Vif protein and the host cells can form a variety of protein complex with ubiquitin protein ligase function, which lead that APOBEC3G was eventually identified and degraded by proteasome. In this study, the action mode between the long peptide inhibitor and the Vif-Elongin C protein was investigated by means of Molecular dynamics simulation method, Molecular docking method and QM/MM. From the theoretical simulation results, it was concluded that the long peptide inhibitor could combined with Elongin C protein stably. Moreover, the binding sites were further confirmed by the way of mutating alanine. The conclusion was drawn that the competitively binding between the long peptide inhibitor and Vif-Elongin C protein inhibited the interaction between Vif-Elongin C protein and APOBEC3G.