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Proc Natl Acad Sci U S A. 2014 Jul 1;111(26):E2656-65. doi: 10.1073/pnas.1401131111. Epub 2014 Jun 17.

Origins of specificity and affinity in antibody-protein interactions.

Author information

1
Genomics Research Center, Academia Sinica, Taipei 115, Taiwan;Institute of Biomedical Informatics, National Yang-Ming University, Taipei 11221, Taiwan; andBioinformatics Program, Taiwan International Graduate Program, Institute of Information Science, Academia Sinica, Taipei 115, Taiwan.
2
Genomics Research Center, Academia Sinica, Taipei 115, Taiwan;
3
Genomics Research Center, Academia Sinica, Taipei 115, Taiwan; yangas@gate.sinica.edu.tw.

Abstract

Natural antibodies are frequently elicited to recognize diverse protein surfaces, where the sequence features of the epitopes are frequently indistinguishable from those of nonepitope protein surfaces. It is not clearly understood how the paratopes are able to recognize sequence-wise featureless epitopes and how a natural antibody repertoire with limited variants can recognize seemingly unlimited protein antigens foreign to the host immune system. In this work, computational methods were used to predict the functional paratopes with the 3D antibody variable domain structure as input. The predicted functional paratopes were reasonably validated by the hot spot residues known from experimental alanine scanning measurements. The functional paratope (hot spot) predictions on a set of 111 antibody-antigen complex structures indicate that aromatic, mostly tyrosyl, side chains constitute the major part of the predicted functional paratopes, with short-chain hydrophilic residues forming the minor portion of the predicted functional paratopes. These aromatic side chains interact mostly with the epitope main chain atoms and side-chain carbons. The functional paratopes are surrounded by favorable polar atomistic contacts in the structural paratope-epitope interfaces; more that 80% these polar contacts are electrostatically favorable and about 40% of these polar contacts form direct hydrogen bonds across the interfaces. These results indicate that a limited repertoire of antibodies bearing paratopes with diverse structural contours enriched with aromatic side chains among short-chain hydrophilic residues can recognize all sorts of protein surfaces, because the determinants for antibody recognition are common physicochemical features ubiquitously distributed over all protein surfaces.

KEYWORDS:

epitope prediction; functional epitope; interface hot spot; paratope prediction; protein antigenic site

PMID:
24938786
PMCID:
PMC4084487
DOI:
10.1073/pnas.1401131111
[Indexed for MEDLINE]
Free PMC Article

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