Structural Consensus among Antibodies Defines the Antigen Binding Site

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Abstract
The Complementarity Determining Regions (CDRs) of antibodies are assumed to account for the antigen recognition and binding and thus to contain also the antigen binding site. CDRs are typically discerned by searching for regions that are most different, in sequence or in structure, between different antibodies. Here, we show that ∼20% of the antibody residues that actually bind the antigen fall outside the CDRs. However, virtually all antigen binding residues lie in regions of structural consensus across antibodies. Furthermore, we show that these regions of structural consensus which cover the antigen binding site are identifiable from the sequence of the antibody. Analyzing the predicted contribution of antigen binding residues to the stability of the antibody-antigen complex, we show that residues that fall outside of the traditionally defined CDRs are at least as important to antigen binding as residues within the CDRs, and in some cases, they are even more important energetically. Furthermore, antigen binding residues that fall outside of the structural consensus regions but within traditionally defined CDRs show a marginal energetic contribution to antigen binding. These findings allow for systematic and comprehensive identification of antigen binding sites, which can improve the understanding of antigenic interactions and may be useful in antibody engineering and B-cell epitope identification. Antibodies are a primary adaptive defence mechanism against infection, and function by recognizing and binding to non-self antigens. While most of the sequence of all antibodies of a given individual is identical, relatively small variations turn each antibody into a specific binder of one antigen. It is widely assumed that antigen binding sites correspond to the so called Complementarity Determining Regions (CDRs) of the antibody, which are defined as the elements that are most different between antibodies. We analysed all known antibody-antigen complexes and found that about 20% of the residues that actually bind the antigen fall outside the CDRs. However, we also found that virtually all antigen binding residues fall within regions of structural consensus between antibodies. Moreover, we demonstrate that antigen binding residues that reside within these structural consensus regions but outside of the traditionally-defined CDRs make significant energetic contribution to antigen binding. Furthermore, we show that these regions are organized along the sequence of the antibody chains and are identifiable from the sequence of the antibody.

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