The indistinguishability of epitopes from protein surface is explained by the distinct binding preferences of each of the six antigen-binding loops

Kunik, Vered; Ofran, Yanay

doi:10.1093/protein/gzt027

Cited by 96vaccines and immunoinformatics approachesMonoclonal and Polyclonal Antibodies ResearchProtein Structure and Dynamics

The indistinguishability of epitopes from protein surface is explained by the distinct binding preferences of each of the six antigen-binding loops

Kunik, Vered, Ofran, Yanay·2013·Protein Engineering Design and Selection

DOI 10.1093/protein/gzt027

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Abstract

General protein-protein interfaces are known to be enriched, compared with other surface patches, with amino acids that can form stabilizing interactions. However, several studies reported that there are hardly any differences between the amino acid composition of B-cell epitopes and that of antigen surface residues. If the amino acid composition of epitopes is indistinguishable from other surface patches, how do antibodies (Abs) identify epitopes? Here, we analyze the antigen binding regions (ABRs, roughly corresponding to the complementarity determining regions) and the epitopes in a non-redundant set of all known Ab-antigen complexes. We find that the ABRs differ significantly from each other in their amino acid composition and length. Analysis of the energetic contribution of each ABR to antigen binding reveals that, while H3 often plays a key role in antigen binding, in many antibodies other ABRs are more important. Moreover, each ABR has a distinct propensity to bind different amino acids on the antigen. The combined binding preferences of the ABRs yield a total preference to amino acids with a composition that is virtually identical to that of surface residues. These results suggest that antibodies evolved to recognize protein surfaces. They may help in improving Ab engineering and B-cell epitope prediction.

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Arbitrary molecular surfaces appear to be indistinguishable from epitope regions, suggesting that predictions should be performed with reference to a particular antibody.
“However, arbitrary molecular surfaces appear to be indistinguishable from epitope regions [167–169] suggesting that predictions should be performed with reference to a particular antibody [116, 118–120].”
From Computational approaches to therapeutic antibody design: established methods and emerging trends (2020) · cites this paper as [167]

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Authors: Kunik, V., & Ofran, Y.
Affiliations: Bar-Ilan University (IL)
Venue: Protein Engineering Design and Selection
Publisher: Oxford University Press (OUP)
Published: 2013-06-10
Volume: 26
Issue: 10
Pages: 599-609
ISSN: 0269-2139 (ISSN-L)
1741-0134
1741-0126
DOI: 10.1093/protein/gzt027
OpenAlex: W2132514101
Cited by: 96
References: 71
Citations by year: 2026: 3 · 2025: 4 · 2024: 5 · 2023: 6 · 2022: 6 · 2021: 9 · 2020: 8 · 2019: 13 · 2018: 7 · 2017: 10 · 2016: 7 · 2015: 9 · 2014: 7 · 2013: 2
FWCI: 3.73
Type: journal article
Language: en
Open access: closed
Locations: Protein Engineering Design and Selection (publishedVersion)
PubMed (publishedVersion)
Topics: Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › vaccines and immunoinformatics approaches
Health Sciences › Medicine › Radiology, Nuclear Medicine and Imaging › Monoclonal and Polyclonal Antibodies Research
Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Structure and Dynamics
Keywords: B-cell epitopes, antigen-binding region, hypervariable region, immune complexes, amino acid composition, epitope prediction, antibody engineering, protein-protein interfaces
MeSH terms: Antibodies, Antibody Specificity, Epitopes, Computational Biology

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The indistinguishability of epitopes from protein surface is explained by the distinct binding preferences of each of the six antigen-binding loops

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