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, leading to a distinct protein corona, 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.

We study the correlation length of the charge-charge pair correlations in concentrated electrolyte solutions by means of all-atom, explicit-solvent molecular dynamics simulations. We investigate LiCl and NaI in water, which constitute highly soluble, prototypical salts for experiments, as well as two more complex, molecular electrolyte systems of lithium bis(trifluoromethane)sulfonimide (LiTFSI), a salt commonly employed in electrochemical storage systems, in water and in an organic solvent mixture of dimethoxyethane (DME) and dioxolane (DOL). Our simulations support the recent experimental observations as well as theoretical predictions of a non-monotonic behavior of the correlation length with increasing salt concentration. We observe a Debye-Hückel like regime at low concentration, followed by a minimum reached when d/ D ' 1, where D is the Debye correlation length and d the e↵ective ionic diameter, and an increasing correlation length with salt concentration in very concentrated electrolytes. As in the experiments, we find that the screening length in the concentrated regime follows a universal scaling law as a function d/ D for all studied salts. However, the scaling exponent is significantly lower than the experimentally measured one, and lies in the range of the theoretical predictions based on much simpler electrolyte models.

Macromolecules based on dendritic or hyperbranched polyelectrolytes have been emerging as high potential candidates for biomedical applications.

When a highly charged globular macromolecule, such as a dendritic polyelectrolyte or charged nanogel, is immersed into a physiological electrolyte solution, monovalent and divalent counterions from the solution bind to the macromolecule in a certain ratio and thereby almost completely electroneutralize it. For charged macromolecules in biological media, the number ratio of bound monovalent vs divalent ions is decisive for the desired function. A theoretical prediction of such a sorption ratio is challenging because of the competition of electrostatic (valency), ion-specific, and binding saturation effects. Here, we devise and discuss a few approximate models to predict such an equilibrium sorption ratio by extending and combining established electrostatic binding theories such as Donnan, Langmuir, Manning, and Poisson–Boltzmann approaches, to systematically study the competitive uptake of monovalent and divalent counterions by the macromolecule. We compare and fit our models to coarse-grained (implicit-solvent) computer simulation data of the globular polyelectrolyte dendritic polyglycerol sulfate (dPGS) in salt solutions of mixed valencies. The dPGS molecule has high potential to serve in macromolecular carrier applications in biological systems and at the same time constitutes a good model system for a highly charged macromolecule. We finally use the simulation-informed models to extrapolate and predict electrostatic features such as the effective charge as a function of the divalent ion concentration for a wide range of dPGS generations (sizes).