Identification Of The Key Residues In Protein Conformational Motions By Using The Simplified Model Combined With A Perturbation Method

In the post genomic era,the study of protein structure-function relationship has been one of the most important scientific problems in the field of bioinformatics.The developments of experimental technologies,such as X-ray crystallography,nuclear magnetic resonance,cryo-electron microscopy,et al.,enables the protein tertiary structure data to increase sharply.However,how to predict the functional motions of protein from its structure and identify the key sits related to the functional motions have attracted the attention of many researchers,and many theoretical models have been proposed.The elastic network model(ENM)method has been proved to be a simple and efficient theoretical method to investigate the conformational motions in proteins.We have developed an internal-coordinates-based ENM method,in which an internal coordinate directly related to the protein specific function was introduced into the model.Our method has been successfully used to study protein functional motions.In this thesis,the internal-coordinates-based ENM method combined with a linear perturbation method was applied to identify the key residues controlling protein specific functional motions.We selected two protein systems,i.e.,human DNA polymerase β and the chaperonin from Methanococcus maripaludies,for research.The calculated results are consistent with the experimental data.Our study provided the physical mechanism of the role of the key sites in the functional motions of proteins.And then,several different internal coordinates were selected in our calculations,and the influences of different internal coordinates on the calculation results were discussed.It is found that the similar results were obtained by using different collective internal coordinates,such as the gyration radius of the protein structure,the distance between different domains,the angle formed by different domains,the volume of the catalysis pocket,etc.The functionally key residues identified by these collective coordinates are located at the similar positions in protein structure.Whereas,for the local internal coordinates such as the distance between different residues,the angle formed by different residues and the changes in the MSF of the functional residues,etc.,the predicted key sites were mainly located at the region near to the coordinate-involving residues.In addition,the internal-coordinates-based ENM method was applied to investigate the structure-encoded conformational motions of the vacuolating cytotoxin A(VacA)secreted by Helicobacter pylori(H.pylori).Several normal motion modes related to VacA functions were obtained.It is found that these conformation motions are related to the host cell infection,lipid bilayer insertion,the formation of ion cannel,and the open-closed motion of the ion channel.Then,several key residues related to functional motions were identified by using the linear perturbation method.Our studies can reveal the mechanism of protein functions and provide the potential target for drug design.