title: The Intrinsic Dynamics and Unfolding Process of an Antibody Fab Fragment Revealed by Elastic Network Model.
abstract: Antibodies 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 McPC603 are investigated by use of the normal mode analysis of Gaussian network model (GNM). Firstly, the 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 mobility and flexibility of the protein, respectively. It is found that the mobility and flexibility of the constant regions are higher than those of the variable regions, and the six complementarity-determining regions (CDRs) in the variable regions also exhibit relative large mobility and flexibility. The large amplitude motions of the CDRs are considered to be associated with the immune function of the antibody. In addition, the unfolding process of the protein was simulated by iterative use of the GNM. In our method, only the topology of protein native structure is taken into account, and the protein unfolding process is simulated through breaking the native contacts one by one according to the MSFID values between the residues. It is found that the flexible regions tend to unfold earlier. The sequence of the unfolding events obtained by our method is consistent with the hydrogen-deuterium exchange experimental results. Our studies imply that the unfolding behavior of the Fab fragment of antibody McPc603 is largely determined by the intrinsic dynamics of the protein.
authors.affiliation: College of Science, Yanshan University, Qinhuangdao 066004, China. jiguosu@ysu.edu.cn.
authors.forename: Ji-Guo
authors.initials: JG
authors.lastname: Su
authors.affiliation: College of Science, Yanshan University, Qinhuangdao 066004, China. xiaozhangysuniv@163.com.
authors.forename: Xiao
authors.initials: X
authors.lastname: Zhang
authors.affiliation: College of Science, Yanshan University, Qinhuangdao 066004, China. a413140155@163.com.
authors.forename: Xiao-Ming
authors.initials: XM
authors.lastname: Han
authors.affiliation: College of Science, Yanshan University, Qinhuangdao 066004, China. zsx360@yeah.net.
authors.forename: Shu-Xin
authors.initials: SX
authors.lastname: Zhao
authors.affiliation: College of Life Science and Bioengineering, Beijing University of Technology, Beijing 100024, China. chunhuali@bjut.edu.cn.
authors.forename: Chun-Hua
authors.initials: CH
authors.lastname: Li
mesh_terms: D000906:Antibodies / Q000737:chemistry*; D004548:Elasticity; D006801:Humans; D008962:Models, Theoretical; D058767:Protein Unfolding
chemical_list: D000906:Antibodies; C069242:McPC603 antibody
keywords: Gaussian network model; fab fragment of antibody McPC603; intrinsic dynamics; native structural topology; unfolding process