title: Promiscuous antibodies characterised by their physico-chemical properties: From sequence to structure and back.
abstract: Human B cells produce antibodies, which bind to their cognate antigen based on distinct molecular properties of the antibody CDR loop. We have analysed a set of 10 antibodies showing a clear difference in their binding properties to a panel of antigens, resulting in two subsets of antibodies with a distinct binding phenotype. We call the observed binding multiplicity 'promiscuous' and selected physico-chemical CDRH3 characteristics and conformational preferences may characterise these promiscuous antibodies. To classify CDRH3 physico-chemical properties playing a role in their binding properties, we used statistical analyses of the sequences annotated by Kidera factors. To characterise structure-function requirements for antigen binding multiplicity we employed Molecular Modelling and Monte Carlo based coarse-grained simulations. The ability to predict the molecular causes of promiscuous, multi-binding behaviour would greatly improve the efficiency of the therapeutic antibody discovery process.
authors.affiliation: Randall Division of Cell and Molecular Biophysics, King's College London, UK.
authors.forename: Julie M J
authors.initials: JMJ
authors.lastname: Laffy
authors.affiliation: Department of Immunobiology, King's College London, UK.
authors.forename: Tihomir
authors.initials: T
authors.lastname: Dodev
authors.affiliation: Randall Division of Cell and Molecular Biophysics, King's College London, UK.
authors.forename: Jamie A
authors.initials: JA
authors.lastname: Macpherson
authors.affiliation: Department of Immunobiology, King's College London, UK.
authors.forename: Catherine
authors.initials: C
authors.lastname: Townsend
authors.affiliation: Randall Division of Cell and Molecular Biophysics, King's College London, UK.
authors.forename: Hui Chun
authors.initials: HC
authors.lastname: Lu
authors.affiliation: Department of Immunobiology, King's College London, UK; Faculty of Health and Medical Sciences, University of Surrey, UK.
authors.forename: Deborah
authors.initials: D
authors.lastname: Dunn-Walters
authors.affiliation: Randall Division of Cell and Molecular Biophysics, King's College London, UK. Electronic address: franca.fraternali@kcl.ac.uk.
authors.forename: Franca
authors.initials: F
authors.lastname: Fraternali
mesh_terms: D000906:Antibodies / Q000737:chemistry* / Q000276:immunology*; D000918:Antibody Specificity; D000941:Antigens / Q000276:immunology; D055598:Chemical Phenomena; D022801:Complementarity Determining Regions / Q000737:chemistry; D006801:Humans; D008958:Models, Molecular; D009010:Monte Carlo Method; D010641:Phenotype; D000072757:Protein Conformation, beta-Strand
chemical_list: D000906:Antibodies; D000941:Antigens; D022801:Complementarity Determining Regions
keywords: Antibody CDRH3; Binding promiscuity; Conformational preferences; ELISA; Kidera factors; Molecular modelling; Monte Carlo simulations