Abstract
Identifying the epitope of an antibody is a key step in understanding its function and its potential as a therapeutic. Sequence-based clonal clustering can identify antibodies with similar epitope complementarity, however, antibodies from markedly different lineages but with similar structures can engage the same epitope. We describe a novel computational method for epitope profiling based on structural modelling and clustering. Using the method, we demonstrate that sequence dissimilar but functionally similar antibodies can be found across the Coronavirus Antibody Database, with high accuracy (92% of antibodies in multiple-occupancy structural clusters bind to consistent domains). Our approach functionally links antibodies with distinct genetic lineages, species origins, and coronavirus specificities. This indicates greater convergence exists in the immune responses to coronaviruses than is suggested by sequence-based approaches. Our results show that applying structural analytics to large class-specific antibody databases will enable high confidence structure-function relationships to be drawn, yielding new opportunities to identify functional convergence hitherto missed by sequence-only analysis.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Amino Acid Sequence
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Animals
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Antibodies, Neutralizing / chemistry
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Antibodies, Neutralizing / genetics
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Antibodies, Viral / chemistry
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Antibodies, Viral / genetics
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Antibodies, Viral / metabolism
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Antibody Specificity
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Antigen-Antibody Complex / chemistry
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Antigen-Antibody Complex / genetics
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Antigen-Antibody Reactions / genetics
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Antigen-Antibody Reactions / immunology
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Antigens, Viral / chemistry*
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COVID-19 / immunology*
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COVID-19 / virology*
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Computational Biology
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Coronavirus / chemistry
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Coronavirus / genetics
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Coronavirus / immunology
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Databases, Chemical
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Epitope Mapping
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Epitopes, B-Lymphocyte / chemistry*
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Epitopes, B-Lymphocyte / genetics
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Humans
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Mice
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Models, Molecular
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Pandemics
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SARS-CoV-2 / chemistry*
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SARS-CoV-2 / genetics
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SARS-CoV-2 / immunology*
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Single-Domain Antibodies / immunology
Substances
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Antibodies, Neutralizing
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Antibodies, Viral
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Antigen-Antibody Complex
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Antigens, Viral
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Epitopes, B-Lymphocyte
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Single-Domain Antibodies
Grants and funding
This work was supported by an Engineering and Physical Sciences Research Council and Medical Research Council Grant [EP/L016044/1] (MR, SR, WW) and further research funding from F. Hoffmann-La Roche (MR, WW), AstraZeneca plc (CS, MR), GlaxoSmithKline plc (MR) and UCB Pharma Ltd. (MR, SR, WW). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.