Designing Multivalent Polymers to be Broad Spectrum Inhibitors, A Computational Study

Mucins, glycoprotein polymers found in mucus, play a key role in protecting us from pathogens by using multiple sugar binding sites simultaneously to create strong multivalent binding interactions. Synthetic glycopolymers have had similar success inhibiting specific toxins, but single polymers have not been able to inhibit two species at once to approach the broad-spectrum protection of native mucins. It remains unclear how the inhibitor structure and binding site arrangement influences its overall binding affinity for substrates. To explore the effect of multivalent polymer structure, we use a Brownian dynamics bead-spring model coupled with a reactive polymer-pathogen binding model to investigate how variables such as degree of polymerization, binding site affinity, and binding site patterns influence a polymeric inhibitor’s affinity for a model substrate. We found that increasing inhibitor length has limited benefit, while increasing individual binding site variety can improve total polymer binding affinities over uniform binding site analogs. Our results suggest design rules for creating broad-spectrum polymeric inhibitors.