Dependence of Avidity on Linker Length for a Bivalent Ligand–Bivalent Receptor Model System
- 16 November 2011
- journal article
- research article
- Published by American Chemical Society (ACS) in Journal of the American Chemical Society
- Vol. 134 (1), 333-345
- https://doi.org/10.1021/ja2073033
Abstract
This paper describes a synthetic dimer of carbonic anhydrase, and a series of bivalent sulfonamide ligands with different lengths (25 to 69 Å between the ends of the fully extended ligands), as a model system to use in examining the binding of bivalent antibodies to antigens. Assays based on analytical ultracentrifugation and fluorescence binding indicate that this system forms cyclic, noncovalent complexes with a stoichiometry of one bivalent ligand to one dimer. This dimer binds the series of bivalent ligands with low picomolar avidities (Kdavidity = 3–40 pM). A structurally analogous monovalent ligand binds to one active site of the dimer with Kdmono = 16 nM. The bivalent association is thus significantly stronger (Kdmono/Kdavidity ranging from ∼500 to 5000 unitless) than the monovalent association. We infer from these results, and by comparison of these results to previous studies, that bivalency in antibodies can lead to associations much tighter than monovalent associations (although the observed bivalent association is much weaker than predicted from the simplest level of theory: predicted Kdavidity of ∼0.002 pM and Kdmono/Kdavidity ∼ 8 × 106 unitless).Keywords
This publication has 38 references indexed in Scilit:
- Fluoroalkyl and Alkyl Chains Have Similar Hydrophobicities in Binding to the “Hydrophobic Wall” of Carbonic AnhydraseJournal of the American Chemical Society, 2011
- Using Covalent Dimers of Human Carbonic Anhydrase II To Model Bivalency in ImmunoglobulinsJournal of the American Chemical Society, 2011
- Carbonic Anhydrase as a Model for Biophysical and Physical-Organic Studies of Proteins and Protein−Ligand BindingChemical Reviews, 2008
- A Synthetic Trivalent Hapten that Aggregates anti-2,4-DNP IgG into Bicyclic TrimersJournal of the American Chemical Society, 2007
- Dependence of Effective Molarity on Linker Length for an Intramolecular Protein−Ligand SystemJournal of the American Chemical Society, 2007
- The Paradoxical Thermodynamic Basis for the Interaction of Ethylene Glycol, Glycine, and Sarcosine Chains with Bovine Carbonic Anhydrase II: An Unexpected Manifestation of Enthalpy/Entropy CompensationJournal of the American Chemical Society, 2006
- Binding Affinities of Host–Guest, Protein–Ligand, and Protein–Transition‐State ComplexesAngewandte Chemie-International Edition, 2003
- Polyvalent Interactions in Biological Systems: Implications for Design and Use of Multivalent Ligands and InhibitorsAngewandte Chemie-International Edition, 1998
- The Fc Segment of IgE Influences the Kinetics of Dissociation of a Symmetrical Bivalent Ligand from Cyclic Dimeric ComplexesBiochemistry, 1996
- Intrachain end-to-end charge transfer interaction in oligosarcosinesPeptide Science, 1981