Quantitative Prediction of Multivalent Ligand-Receptor Binding Affinities for Influenza, Cholera and Anthrax Inhibition

Multivalency achieves strong, yet reversible binding by the simultaneous formation of multiple weak bonds. It is a key interaction principle in biology and promising for the synthesis of high-affinity inhibitors of pathogens. We present a model for the binding affinity of synthetic multivalent ligands onto multivalent receptors consisting of n receptor units arranged on a regular polygon. Ligands consist of a rigid polygonal core to which monovalent ligand units are attached via flexible linker polymers. The calculated binding affinities quantitatively agree with experimental studies for cholera toxin (n=5) and anthrax receptor (n=7). We find that maximal binding affinity is achieved for a core that matches the receptor size and for linkers that have an equilibrium end-to-end distance that is slightly larger than the difference between core-size and receptor-size. We compare mono- and multivalent binding affinities, from which we conclude that multivalent ligands against influenza viral hemagglutinin (n=3), cholera toxin (n=5) and anthrax receptor (n=7) can outperform monovalent ligands only for a monovalent ligand affinity that exceeds a core-size dependent threshold value.