Adsorption of Mono- and Divalent Ions onto Dendritic Polyglycerol Sulfate (dPGS) as Studied Using Isothermal Titration Calorimetry

The effective charge of highly charged polyelectrolytes is significantly lowered by a condensation of counterions. This effect is more pronounced for divalent ions. Here we present a study of the counterion condensation to dendritic polyglycerol sulfate (dPGS) that consists of a hydrophilic dendritic scaffold onto which sulfate groups are appended. The interactions between the dPGS and divalent ions (Mg2+ and Ca2+) were analyzed using isothermal titration calorimetry (ITC) and showed no ion specificity upon binding, but clear competition between the monovalent and divalent ions. Our findings, in line with the latest theoretical studies, demonstrate that a large fraction of the monovalent ions is sequentially replaced with the divalent ions

Highly charged dendritic polyelectrolytes: Competitive ion binding and charge renormalization

Polyelektrolyte (PEs) bilden eine große Klasse von Materialien, die in der wissenschaftlichen Forschung immer mehr Beachtung findet. Aufgrund der Lange-Bereich Elektrostatic ist das theoretische Verständnis von PE-Lösungen im Vergleich zu ihren neutralen Gegenstücken noch relativ schlecht gewesen, dadurch die Rationalisierung der Gegenionskondensation auf hochgeladenen PEs herausfordern. Die Komplexität des Problems wird noch zusätzlich durch die gleichzeitige Anwesenheit monovalenter und divalenter Gegenionen in der Lösung, was vielen biologische Umgebungen entspricht, erhöht. Dies beeinflusst die PE-Protein Komplexierungen, damit ihren Funktionen und Anwendungen in der Biomedizin und Biotechnologie. In dieser Arbeit führen wir eine umfassende Analyse der Ladungs- und Hydratationsstruktur von dendritischen PEs in einem monovalenten Salz unter Verwendung von atomistischen Molekulardynamik (MD) Computersimulationen mit explizitem Wasser durch. Darüber hinaus untersuchen der kompetitiven Adsorption der monovalenten und divalenten Gegenionen am globulären PE mit Hilfe theoretischer Mean-Field-Modelle, vergröberter und atomistischer (expliziter) Wasser-Simulationen und Kalorimetrie-Experimenten. Wir befassen uns mit der Herausforderung, eine genau definierte effektive Ladung und ein Oberflächenpotential der PEs für praktische Anwendungen zu finden, und präsentieren ein neuartiges kompetitives Ionenbindungsmodell, das einen aussagekräftigen Vergleich zwischen Theorie, Simulationen und Experimenten gewährleistet. Diese Arbeit stellt eine systematische elektrostatischen Beschreibung von PE vor, untersucht die thermodynamische PE-Wasser Signatur und analysiert die kompetitiven Bindung von monovalenten und divalenten Gegenionen an PEs. Es wird ein tieferer Einblick in die physikochemischen Aspekte von PE-Gegenionen- und PE-Wasser-Wechselwirkungen erhalten, was für das rationale Design von PEs auf einer gezielten Anwendungsbasis von entscheidender Bedeutung ist.Polyelectrolytes (PEs) represent a broad class of materials that are getting an increasing attention in the scientific community. However, due to the long-range electrostatics, the theoretical understanding of PE solutions has been relatively poor compared to their neutral counterparts, thereby challenging the rationalization of the counterion condensation on highly charged PEs. Moreover, the counter-intuitive footprint of PE-water thermodynamics, and the simultaneous presence of the divalent and the monovalent counterions in the solution, as is reminiscent of many biological environments, escalates the complexity and richness of the problem. This affects the PE-proteins complexations, and thus their functions, applications in biomedicine and biotechnology. In this thesis, we conduct a comprehensive analysis of the charge and hydration structure of dendritic PEs in a monovalent salt using all-atom explicit-water molecular dynamics computer simulations, and investigate a competitive sorption of mono- versus divalent ions on globular PEs using mean-field theoretical models, all-atom and coarse-grained simulations and calorimetry experiments. We address the challenges of obtaining a well-defined effective charge and surface potential of the PE for practical applications and present a novel competitive ion binding model, ensuring a meaningful comparison between theory, simulations and experiments. This thesis lays out a systematic PE electrostatic characterization, explores PE-water thermodynamics, and analyses the competitive binding of divalent and monovalent counterions on the PE. A deeper insight into the physicochemical aspects of PE-counterion and PE-water interactions is achieved, which is vital towards the rational design of PEs on a targeted application basis

Correlation Length in Concentrated Electrolytes: Insights from All-Atom Molecular Dynamics Simulations

We study the correlations 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), 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/λD = 1, where λD is the Debye correlation length and d the effective 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/λD 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. </div

Counterion-Release Entropy Governs the Inhibition of Serum Proteins by Polyelectrolyte Drugs

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

Retrotransposons Are the Major Contributors to the Expansion of the Drosophila ananassae Muller F Element

The discordance between genome size and the complexity of eukaryotes can partly be attributed to differences in repeat density. The Muller F element (∼5.2 Mb) is the smallest chromosome in Drosophila melanogaster, but it is substantially larger (>18.7 Mb) in D. ananassae. To identify the major contributors to the expansion of the F element and to assess their impact, we improved the genome sequence and annotated the genes in a 1.4-Mb region of the D. ananassae F element, and a 1.7-Mb region from the D element for comparison. We find that transposons (particularly LTR and LINE retrotransposons) are major contributors to this expansion (78.6%), while Wolbachia sequences integrated into the D. ananassae genome are minor contributors (0.02%). Both D. melanogaster and D. ananassae F-element genes exhibit distinct characteristics compared to D-element genes (e.g., larger coding spans, larger introns, more coding exons, and lower codon bias), but these differences are exaggerated in D. ananassae. Compared to D. melanogaster, the codon bias observed in D. ananassae F-element genes can primarily be attributed to mutational biases instead of selection. The 5′ ends of F-element genes in both species are enriched in dimethylation of lysine 4 on histone 3 (H3K4me2), while the coding spans are enriched in H3K9me2. Despite differences in repeat density and gene characteristics, D. ananassae F-element genes show a similar range of expression levels compared to genes in euchromatic domains. This study improves our understanding of how transposons can affect genome size and how genes can function within highly repetitive domains