title: Free energy perturbation approach for the rational engineering of the antibody for human hepatitis B virus.
abstract: HzKR127 is the humanized monoclonal antibody effective for the neutralization of human hepatitis B virus. By means of the free energy perturbation (FEP) calculations based on molecular dynamic (MD) simulations, we examine the mutation-induced variations in the energetic and structural features associated with the interactions between HzKR127 and its antigen. N58A, Y96A, D97A, and D97A/Y102A mutants of HzKR127 are taken in account in this study for which the experimental data for relative efficacies with respect to the wild-type antibody are available. The results of the present MD-FEP simulation studies show that in order to enhance the affinity for the antigen, the engineering of HzKR127 should be made in such a way as to promote the dynamic stability of the overall protein conformation and that of the translational motion of the antigen in the antibody-antigen complex. The relative binding free energies of the four mutant antibodies obtained from MD-FEP calculations compare pretty well with the experimental mutagenesis data with the associated squared correlation coefficient of 0.96. This indicates that MD-FEP calculations may serve as a useful computational tool for rational antibody engineering. Discussed in detail are the differences in the structural features of antibody-antigen interactions between the wild-type and the mutant antibodies that are responsible for the change in binding affinities for the antigen.
authors.affiliation: Department of Bioscience and Biotechnology, Sejong University, 98 Kunja-Dong, Kwangjin-Ku, Seoul 143-747, Republic of Korea. hspark@sejong.ac.kr
authors.forename: Hwangseo
authors.initials: H
authors.lastname: Park
authors.forename: Young Ho
authors.initials: YH
authors.lastname: Jeon
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal / Q000737:chemistry* / Q000235:genetics / Q000276:immunology*; D003198:Computer Simulation; D006515:Hepatitis B virus / Q000737:chemistry* / Q000276:immunology*; D006801:Humans; D008958:Models, Molecular; D015394:Molecular Structure; D011487:Protein Conformation; D015202:Protein Engineering; D013816:Thermodynamics
chemical_list: D000911:Antibodies, Monoclonal