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

TL;DR

This study reveals that counterion-release entropy is the main factor governing the binding of dendritic polyelectrolyte drugs to serum proteins, enabling better rational design of such therapeutic agents.

Contribution

It demonstrates that protein-polyelectrolyte interactions can be accurately predicted by simulations focusing on counterion-release mechanisms, advancing drug design.

Findings

Counterion-release drives strong protein-polyelectrolyte complexation.

Binding affinity is weakly dependent on polyelectrolyte size due to charge-renormalization.

Selectivity of P- and L-selectins over E-selectin explained by interfacial charge structure.

Abstract

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.