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Dendritic polyelectrolytes constitute high potential drugs and carriersystems for biomedical purposes, still their biomolecular interaction modes, inparticular those determining the binding affinity to proteins, have not beenrationalized. We study the interaction of the drug candidate dendriticpolyglycerol sulfate (dPGS) with serum proteins using Isothermal TitrationCalorimetry (ITC) interpreted and complemented with molecular computersimulations. Lysozyme is first studied as a well-defined model protein toverify theoretical concepts, which are then applied to the important celladhesion protein family of selectins. We demonstrate that the driving force ofthe strong complexation originates mainly from the release of only a fewcondensed counterions from the dPGS upon binding. The binding constant shows asurprisingly weak dependence on dPGS size (and bare charge) which can beunderstood by colloidal charge-renormalization effects and by the fact that themagnitude of the dominating counterion-release mechanism almost exclusivelydepends on the interfacial charge structure of the protein-specific bindingpatch. Our findings explain the high selectivity of P- and L- selectins overE-selectin for dPGS to act as a highly anti-inflammatory drug. The entireanalysis demonstrates that the interaction of proteins with charged polymericdrugs can be predicted by simulations with unprecedented accuracy. Thus, ourresults open new perspectives for the rational design of charged polymericdrugs and carrier systems.

Counterion-release entropy governs the inhibition of serum proteins by polyelectrolyte drugs