Study On Protein Functional Motions And Unfolding Process With Elastic Network Model

The research of structure and functional motions of proteins is one of the key scientific problems in the field of bioinformatics. In order to understand the internal mechanism of the biological function of the protein, it is not enough to know the structure information, but also the structural encoded dynamic information. How to start from the protein structure and predict its function related movement patterns and identify the key residues is an important topic worthy of study. In addition, due to their low toxicity and high efficiency, antibodies are growingly used as pharmaceuticals for the prevention and treatment of various diseases. The investigation of antibody unfolding process is helpful for our understanding the physicalmechanism of antibody stability and provides valuable information for antibody design. In this thesis, some works have been done in the two central study fields mentioned above. The main study contents in this work consist of the following two aspects: 1. Functional motions studies of Vitamin B12 tansporter based on Elastic Network ModelBtu CD–Btu F is a type II ABC transporter system that uses the energy of ATP to translocate vitamin B12 from the periplasm to the cytoplasm of Escherichia coli. In the present work, the extent of opening of the cytoplasmic gate was chosen as a function-related internal coordinate. Then the mean-square fluctuation of the internal coordinate, as well as the cross-correlation between the displacement of the internal coordinate and the movement of each residue in the protein, were calculated based on the normal mode analysis of the elastic network model to analyze the function-related motions encoded in the structure of the system. In addition, the key residues important for the functional motions of the transporter were predicted by using a perturbation method. 2. The intrinsic dynamics and unfolding process of an antibody Mc PC603 Fab fragmentAntibodies have been increasingly used as pharmaceuticals in clinical treatment. Thermal stability and unfolding process are important properties that must be considered in antibody design. In this paper, the structure-encoded dynamical properties and the unfolding process of the Fab fragment of the phosphocholine-binding antibody Mc PC603 are investigated by use of the normal mode analysis of Gaussian network model(GNM). Firstly, temperature factors for the residues of the protein were calculated with GNM and then compared with the experimental measurements. A good result was obtained, which provides the validity for the use of GNM to study the dynamical properties of the protein. Then, with this approach, the mean-square fluctuation(MSF) of the residues, as well as the MSF in the internal distance(MSFID) between all pairwise residues, was calculated to investigate the mobilityand flexibility of the protein, respectively. In addition, the unfolding process of the protein was simulated by iterative use of the GNM. The sequence of the unfolding events obtained by our method is consistent with the hydrogen-deuterium exchange experimental results.