title: Rationalization and design of the complementarity determining region sequences in an antibody-antigen recognition interface.
abstract: Protein-protein interactions are critical determinants in biological systems. Engineered proteins binding to specific areas on protein surfaces could lead to therapeutics or diagnostics for treating diseases in humans. But designing epitope-specific protein-protein interactions with computational atomistic interaction free energy remains a difficult challenge. Here we show that, with the antibody-VEGF (vascular endothelial growth factor) interaction as a model system, the experimentally observed amino acid preferences in the antibody-antigen interface can be rationalized with 3-dimensional distributions of interacting atoms derived from the database of protein structures. Machine learning models established on the rationalization can be generalized to design amino acid preferences in antibody-antigen interfaces, for which the experimental validations are tractable with current high throughput synthetic antibody display technologies. Leave-one-out cross validation on the benchmark system yielded the accuracy, precision, recall (sensitivity) and specificity of the overall binary predictions to be 0.69, 0.45, 0.63, and 0.71 respectively, and the overall Matthews correlation coefficient of the 20 amino acid types in the 24 interface CDR positions was 0.312. The structure-based computational antibody design methodology was further tested with other antibodies binding to VEGF. The results indicate that the methodology could provide alternatives to the current antibody technologies based on animal immune systems in engineering therapeutic and diagnostic antibodies against predetermined antigen epitopes.
authors.affiliation: Genomics Research Center, Academia Sinica, Taipei, Taiwan.
authors.forename: Chung-Ming
authors.initials: CM
authors.lastname: Yu
authors.forename: Hung-Pin
authors.initials: HP
authors.lastname: Peng
authors.forename: Ing-Chien
authors.initials: IC
authors.lastname: Chen
authors.forename: Yu-Ching
authors.initials: YC
authors.lastname: Lee
authors.forename: Jun-Bo
authors.initials: JB
authors.lastname: Chen
authors.forename: Keng-Chang
authors.initials: KC
authors.lastname: Tsai
authors.forename: Ching-Tai
authors.initials: CT
authors.lastname: Chen
authors.forename: Jeng-Yih
authors.initials: JY
authors.lastname: Chang
authors.forename: Ei-Wen
authors.initials: EW
authors.lastname: Yang
authors.forename: Po-Chiang
authors.initials: PC
authors.lastname: Hsu
authors.forename: Jhih-Wei
authors.initials: JW
authors.lastname: Jian
authors.forename: Hung-Ju
authors.initials: HJ
authors.lastname: Hsu
authors.forename: Hung-Ju
authors.initials: HJ
authors.lastname: Chang
authors.forename: Wen-Lian
authors.initials: WL
authors.lastname: Hsu
authors.forename: Kai-Fa
authors.initials: KF
authors.lastname: Huang
authors.forename: Alex Che
authors.initials: AC
authors.lastname: Ma
authors.forename: An-Suei
authors.initials: AS
authors.lastname: Yang
mesh_terms: D000937:Antigen-Antibody Reactions; D001185:Artificial Intelligence; D001666:Binding Sites, Antibody; D022801:Complementarity Determining Regions; D018360:Crystallography, X-Ray; D006801:Humans; D008958:Models, Molecular; D015203:Reproducibility of Results; D057127:Single-Chain Antibodies / Q000737:chemistry / Q000276:immunology; D042461:Vascular Endothelial Growth Factor A / Q000276:immunology
chemical_list: D022801:Complementarity Determining Regions; D057127:Single-Chain Antibodies; D042461:Vascular Endothelial Growth Factor A