Computational identification of antigen-binding antibody fragments

• Published in: The Journal of immunology (1950) Vol. 190; no. 5; pp. 2327 - 2334
• Main Authors: Burkovitz, Anat, Leiderman, Olga, Sela-Culang, Inbal, Byk, Gerardo, Ofran, Yanay
• Format: Journal Article
• Language: English
• Published: United States 01.03.2013
• Subjects: Animals; Antibody Affinity; Antibody Specificity; Antigen-Antibody Complex - chemistry; Antigen-Antibody Complex - genetics; Antigen-Antibody Complex - immunology; Antigens - chemistry; Antigens - genetics; Antigens - immunology; Binding Sites, Antibody; Chickens; Cloning, Molecular; Complementarity Determining Regions - chemistry; Complementarity Determining Regions - genetics; Complementarity Determining Regions - immunology; Databases, Protein; Escherichia coli - genetics; Humans; Immunoglobulin Heavy Chains - chemistry; Immunoglobulin Heavy Chains - genetics; Immunoglobulin Heavy Chains - immunology; Models, Molecular; Peptides - chemistry; Peptides - genetics; Peptides - immunology; Recombinant Proteins - chemistry; Recombinant Proteins - genetics; Recombinant Proteins - immunology; Single-Chain Antibodies - chemistry; Single-Chain Antibodies - genetics; Single-Chain Antibodies - immunology; Thermodynamics
• ISSN: 0022-1767; 1550-6606
• DOI: 10.4049/jimmunol.1200757

Determining which parts of the Ab are essential for Ag recognition and binding is crucial for understanding B cell-mediated immunity. Identification of fragments of Abs that maintain specificity to the Ag will also allow for the development of improved Ab-based therapy and diagnostics. In this article, we show that structural analysis of Ab-Ag complexes reveals which fragments of the Ab may bind the Ag on their own. In particular, it is possible to predict whether a given CDR is likely to bind the Ag as a peptide by analyzing the energetic contribution of each CDR to Ag binding and by assessing to what extent the interaction between that CDR and the Ag depends on other CDRs. To demonstrate this, we analyzed five Ab-Ag complexes and predicted for each of them which of the CDRs may bind the Ag on its own as a peptide. We then show that these predictions are in agreement with our experimental analysis and with previously published experimental results. These findings promote our understanding of the modular nature of Ab-Ag interactions and lay the foundation for the rational design of active CDR-derived peptides.