  Dendritic polyelectrolytes constitute high potential drugs and carrier
systems for biomedical purposes, still their biomolecular interaction modes, in
particular those determining the binding affinity to proteins, have not been
rationalized. We study the interaction of the drug candidate dendritic
polyglycerol sulfate (dPGS) with serum proteins using Isothermal Titration
Calorimetry (ITC) interpreted and complemented with molecular computer
simulations. Lysozyme is first studied as a well-defined model protein to
verify theoretical concepts, which are then applied to the important cell
adhesion protein family of selectins. We demonstrate that the driving force of
the strong complexation originates mainly from the release of only a few
condensed counterions from the dPGS upon binding. The binding constant shows a
surprisingly weak dependence on dPGS size (and bare charge) which can be
understood by colloidal charge-renormalization effects and by the fact that the
magnitude of the dominating counterion-release mechanism almost exclusively
depends on the interfacial charge structure of the protein-specific binding
patch. Our findings explain the high selectivity of P- and L- selectins over
E-selectin for dPGS to act as a highly anti-inflammatory drug. The entire
analysis demonstrates that the interaction of proteins with charged polymeric
drugs can be predicted by simulations with unprecedented accuracy. Thus, our
results open new perspectives for the rational design of charged polymeric
drugs and carrier systems.
