Investigation On Folding Mechanisms Of Three Kinds Of Proteins With Special Conformations By Theoretical Calculation

Biomacromolecules need to fold into correct three-dimensional structures to perform proper biological functions. Protein and nucleic acid are essential components of protoplasm, and the two molecules are important in organisms. So the research about the folding of protein and nucleic acid chains could give a chance to better understand the related biological functions, and it is meaningful to research the diseases which are relative to the folding of the two kinds of molecules. In the study of the relationship between biological structure and function, the in-depth knowledge about the mechanism of dynamic behavior is meanful to study the functional diversity and design new functional molecules. With the development of theoretical methods, molecular dynamics simulation is playing an increasing role in many fields, such as physics, chemistry and bioscience, and becoming an important method.This article is aimed at studying folding mechanisms of protein and deoxyribonucleic acid (DNA) with structure-based models and molecular dynamics simulations under high temperature. The main works are described as follows:(1) Here we used molecular dynamics simulation with OPLS all-atom force field to study the unfolding processes of GA88, GB88, GA95and GB95under high temperature, and adopted unfolding processes to reverse folding processes for proteins. We also compared the folding mechanisms of these proteins. The GA88/GB88and GA95/GB95are mutants of GA/GB, so we simulated proteins GA/GB with Go-model. In the folding processes of GA88and GA95, the secondary structures formed earlier than the tertiary interactions, and then stacked together gradually to form hydrophobic core. In the folding processes of GB88and GB95, the a-helix formed earlier than β-sheets, and then stacked together to form hydrophobic core. Early along the folding pathway, the final protein structures were determined, and very small differences between protein sequences determine the native states of proteins.(2) Here we used molecular dynamics simulations under high temperature and all-atom Go-model to investigate the folding mechanism for protein MJ0366. Both of the Ca-Go model and all-atom Go model were used to study the folding process of protein VirC2. The two proteins belong to trefoil knots, and both of them have shallow knots. Results show that the contacts formed in β-sheet are important to the formation of knotted protein, if these contacts are disappeared, the knotted protein would be easy to untie. In the simulations of Go-models, the folding processes of the two knotted proteins are similar. The intermediate states for both of the two proteins formed P-sheet with loose C-terminal. At transition state the C-terminal prepared for folding into knot, and some structures formed knot. The Go-model also reveals detailed folding mechanisms for the two proteins.(3) Neurodegenerative diseases have been found from both human and bovine, but the rabbit, canine and horse have no reports about infected by transmissible spongiform encephalopathies. These diseases have a close relation with the conversion from normal to abnormal prion protein, belong to folding disease. Here we used coarse-grained Go model to compare the difference among human, bovine, rabbit, canine and horse normal (cellular) prion proteins, compare the folding mechanisms of the five prion proteins, and analyze these prion proteins from the perspective of cooperativity and folding processes. We hope to get the information about anti-infection from rabbit, canine and horse prion proteins, and further to study the folding mechanisms of the five prion proteins. In the simulations of coarse-grained Go model, the cooperativity of the five prion proteins was characterized in terms of calorimetric criterion, sigmoidal transition, and free-energy profile. The rabbit and horse prion proteins have higher folding free-energy barrier and cooperativity, and canine prion protein has slightly higher folding free-energy barrier comparing with human and bovine prion proteins. The results from all-atom Go model confirmed the validity of Ca-Go model. The correlations of our results with previous experimental and theoretical researches were discussed.(4) In this study, we used energy landscape theory to elucidate folding mechanisms for thrombin aptamer, Form1, Form3and Na+solution G-quadruplexes. The four G-quadruplexes were simulated with all-atom Go-model, and then compared the difference among the four G-quadruplexes from the perspective of folding route and conformation. Results show that, the first three G-quadruplexes through a two-state mechanism fold into native states. In the initial stage of folding process, the compact structures are formed. The G-quadruplexes need to form G-triplex structures on the basis of these formed compact structures before folding into native states. The Na+solution G-quadruplex forms metastable structure at the initial stage of folding process, and then folds into G-triplex structure. The folding free-energy barrier of Form3G-quadruplex is higher than the other three G-quadruplexes, which implies that the structure of Form3G-quadruplex has more stability than the other three G-quadruplexes, this result is the same as the experimental result.The simulation results confirmed experimental results.