The interfacial character of antibody paratopes: analysis of antibody–antigen structures

Nguyen, Minh N. H.; Pradhan, Mohan R.; Verma, Chandra; Zhong, Pingyu

doi:10.1093/bioinformatics/btx389

Cited by 52 publications

(40 citation statements)

References 31 publications

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“…Over the last decades, the increasing amount of antibody-antigen crystal structures has enabled the first quantitative insight into the physicochemical features of antibody-antigen interaction (Benjamin et al, 1984;Berzofsky, 1985;Burkovitz et al, 2013;Dalkas et al, 2014;Lawrence and Colman, 1993;MacCallum et al, 1996;Ofran et al, 2008;Peng et al, 2014;Raghunathan et al, 2012;Sela-Culang et al, 2013;Sivalingam and Shepherd, 2012). For example, it has been observed repeatedly that paratopes localize mostly, but not exclusively, to CDRs (Kunik et al, 2012a), and that certain amino acids are preferentially enriched or depleted in the antibody binding regions (Mian et al, 1991;Nguyen et al, 2017;Ramaraj et al, 2012;Sela-Culang et al, 2013;Wang et al, 2018). For epitopes, several analyses have shown that their amino-acid composition is essentially indistinguishable from that of other surfaceexposed non-epitope residues if the corresponding antibody is not taken into account (Kringelum et al, 2013;Kunik and Ofran, 2013;Ponomarenko and Bourne, 2007).…”

Section: Introductionmentioning

confidence: 99%

A compact vocabulary of paratope-epitope interactions enables predictability of antibody-antigen binding

Akbar

Jeliazkov

Robert

et al. 2019

Preprint

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Antibody recognition of antigen relies on the specific interaction of amino acids at the paratopeepitope interface. A long-standing question in the fields of immunology and structural biology is whether paratope-epitope interaction is predictable. A fundamental premise for the predictability of paratope-epitope binding is the existence of structural units that are universally shared among antibody-antigen binding complexes. Here, we identified structural interaction motifs, which together compose a vocabulary of paratope-epitope binding that is shared among investigated antibody-antigen complexes. The vocabulary (i) is finite with less than 10 4 motifs, (ii) mediates specific and non-redundant interactions between paratope-epitope pairs, (iii) is immunity-specific (distinct from the motif vocabulary used by non-immune protein-protein interactions), and (iv) enables the machine learning prediction of paratope or epitope. The discovery of a vocabulary of paratope-epitope interaction demonstrates the learnability and predictability of paratope-epitope interaction.

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Section: Introductionmentioning

confidence: 99%

A compact vocabulary of paratope-epitope interactions enables predictability of antibody-antigen binding

Akbar

Jeliazkov

Robert

et al. 2019

Preprint

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“…Antibodies are key players as therapeutic agents because of their ability to bind the majority of targets and their suitability for protein engineering. [1][2][3][4] Description of the binding properties 5 and characterization of the paratope 6 is essential for understanding the function of the antibody. In the antigen-binding process, the most important region is the complementarity-determining region (CDR), which consists of six hypervariable loops that shape the paratope.…”

Section: Introductionmentioning

confidence: 99%

CDR-H3 loop ensemble in solution – conformational selection upon antibody binding

Fernández‐Quintero

Kraml

Georges

et al. 2019

mAbs

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We analyzed pairs of protein-binding, peptide-binding and hapten-binding antibodies crystallized as complex and in the absence of the antigen with and without conformational differences upon binding in the complementarity-determining region (CDR)-H3 loop. Here, we introduce a molecular dynamicsbased approach to capture a diverse conformational ensemble of the CDR-H3 loop in solution. The results clearly indicate that the inherently flexible CDR-H3 loop indeed needs to be characterized as a conformational ensemble. The conformational changes of the CDR-H3 loop in all antibodies investigated follow the paradigm of conformation selection, because we observe the experimentally determined binding competent conformation without the presence of the antigen within the ensemble of pre-existing conformational states in solution before binding. We also demonstrate for several examples that the conformation observed in the antibody crystal structure without antigen present is actually selected to bind the carboxyterminal tail region of the antigen-binding fragment (Fab). Thus, special care must be taken when characterizing antibody CDR-H3 loops by Fab X-ray structures, and the possibility that pre-existing conformations are present should always be considered.

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“…The interaction force between molecules mainly depends on hydrophobic interactions, hydrogen bonds, and ionic bonds. The bond energy of hydrophobic interactions is approximately 1~2 kJ/mol, the hydrogen bond force is 1 to 2 times greater, and the ionic bond is the strongest, approximately one order of magnitude higher 29 . Through in-depth analysis of the interface residues, the local environment of the residues can be understood and improved by changing some of the amino acid sites.…”

Section: Resultsmentioning

confidence: 97%

A Highly Sensitive Detection System based on Proximity-dependent Hybridization with Computer-aided Affinity Maturation of a scFv Antibody

Wang

Liang

et al. 2018

Sci Rep

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The hepatitis B virus (HBV) infection is a critical health problem worldwide, and HBV preS1 is an important biomarker for monitoring HBV infection. Previously, we found that a murine monoclonal antibody, mAb-D8, targets the preS1 (aa91-107) fragment of HBV. To improve its performance, we prepared the single-chain variable region of mAb-D8 (scFvD8) and constructed the three-dimensional structure of the scFvD8-preS1 (aa91-107) complex by computer modelling. The affinity of scFvD8 was markedly increased by the introduction of mutations L96Tyr to Ser and H98Asp to Ser. Furthermore, a highly sensitive immunosensor was designed based on a proximity-dependent hybridization strategy in which the preS1 antigen competitively reacts with an antibody labelled with DNA, resulting in decreased proximity-dependent hybridization and increased electrochemical signal from the Fc fragment, which can be used for the quantisation of preS1. The results showed a wide detection range from 1 pM to 50 pM with a detection limit of 0.1 pM. The sensitivity and specificity of this immunosensor in clinical serum samples were 100% and 96%, respectively. This study provides a novel system based on proximity-dependent hybridization and the scFv antibody fragment for the rapid quantisation of antigens of interest with a high sensitivity.

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The interfacial character of antibody paratopes: analysis of antibody–antigen structures

Abstract: Supplementary data are available at Bioinformatics online.

Cited by 52 publications

References 31 publications

A compact vocabulary of paratope-epitope interactions enables predictability of antibody-antigen binding

A compact vocabulary of paratope-epitope interactions enables predictability of antibody-antigen binding

CDR-H3 loop ensemble in solution – conformational selection upon antibody binding

A Highly Sensitive Detection System based on Proximity-dependent Hybridization with Computer-aided Affinity Maturation of a scFv Antibody

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