Identification Of Key Residues In Protein Movements By Using Molecular Dynamics Simulations Combined With A Perturbation Method

Proteins are closely related to our lives as an important part of living organisms,and each protein has its own structure.Study on the protein structure as well as its functional roles in the living organisms is one of the research focuses in the field of structual biology.The realization of protein functional movement is usually accompanied by specific conformational changes,and there exist some key residues that mediate and control the functional motions of proteins in the allosteric process.How to develop effective theoretical models and analytical methods based on protein tertiary structure and use physical principles to determine the protein functional conformational movements and identify the key residues in functional movements are important scientific problems worth researching deeply.In this thesis,the perturbation-response scanning method developed by our group was combined with the molecular dynamics(MD)simulation to identify the key residues controlling the functional movement of proteins.In our method,a physical quantity that is directly related to protein specific function was introduced,and then based on the MD simulation trajectories,the perturbation-response scanning method was used to identify the key residues for functional motions,in which the residues that highly correlated with the fluctuation of the function-related quantity were identified as the key residues controlling the specific functional motions of the protein.Two protein systems,the heat shock protein 70 and glutamine binding protein,were selected as case studies to validate the effectiveness of our method.The key residues predicted by our method are located at the similar regions,which can be grouped into the following locations:(1)The opening of the pocket.(2)The hinge region connecting different subdomains in the protein structure.(3)The substrate binding site.(4)The hinge region responsible for the relative motion between different parts within the subdomains of the proteins.Our calculated results are in good agreement with experimental results.The key residues in the two proteins are similar in location,indicating the similar mechanisms behind the performance of biological functions.Our study is helpful to reveal the molecular mechanism of protein functional movements and provides valuable theoretical support for drug design and diseases treatment.