(357f) Polyacid-Functionalized Gold Nanoparticles As an Amyloid-? Inhibitor Platform

Authors: 
van der Munnik, N. P., University of South Carolina
Mingle, K., University of South Carolina
Wei, T., Lamar University
Lauterbach, J., University of South Carolina
Uline, M. J., University of South Carolina
Moss, M. A., University of South Carolina
Alzheimer’s disease (AD) is a debilitating disease that is the sixth leading cause of death in the United States. Current understanding of the etiology of AD points to disruption of the amyloid-β (Aβ) aggregation pathway as a promising strategy for a potential cure. Functionalized gold nanoparticles (AuNPs) have gained attention as inhibitors of Aβ aggregation. We recently demonstrated that polyacrylic acid-coated (PAA) AuNPs are strong inhibitors of aggregation and proposed that this inhibition results from alterations in solution near the NP surface.

To further probe this hypothesis, spherical AuNPs were synthesized with two different average diameters (5 and 20 nm) and functionalized with PAA having two distinct degrees of polymerization (20 and 80). Using these two levels for these two parameters we obtain four unique AuNP samples. The effect that these functionalized AuNPs have on the aggregation of Aβ was assessed by incubating 10 μM Aβ monomer with 0 (control), 10 or 30 nM AuNPs in 40mM Tris-HCl (pH 8.0) containing 0 or 150 mM NaCl. The extent of aggregation was measured using the fluorescent dye thioflavin T (ThT) over the course of 72 hours. Subsequently, transmission electron microscopy (TEM) images were obtained for the Aβ species present. We have performed an analysis of the results from the two level-four factor full factorial design at varied NP and solution conditions.

We have correlated the results of this factorial analysis to the predictions made using a theoretical model of the polymers and solution near the NP surface. The PAA layer on the AuNPs was modeled with a self-consistent mean field theory that explicitly accounts for the size, shape, conformation and charge distribution of all molecular species present in the aggregation assay buffer. The conditions present in the experiments were used to parameterize the theoretical model. The theory consists of writing the Helmholtz free energy of the system in terms of the entropy and energy associated with all species. A conformational ensemble for the PAA molecules is generated using the rotational isomeric states model (RIS). Thermodynamic equilibrium expressions are derived for the density of each molecular species as a function of distance from the AuNP surface. These equations were solved numerically.

A similar self-consistent field model has been developed for Aβ itself. In this case, the chain molecule of interest is the protein and the conformational ensemble is generated from molecular dynamics simulations. Additionally, the model includes terms to account for the solvation of the protein surface, effectively capturing the hydrophobic properties of the amino acids constituting the molecule. Practical application of the framework involves constraining the centers of mass of the proteins at positions in space and solving the resultant system of thermodynamic equilibrium expressions. This yields a thermodynamic potential reflective of the relative configuration of Aβ molecules, allowing one to evaluate the potential of mean force for dimerization as well as the free energy landscape of the formation of oligomer structures. Moreover, all of this information is calculable in altered solution conditions evoked by the presence of PAA-coated AuNPs.

PAA-functionalized AuNPs displayed a remarkable ability to inhibit the aggregation of Aβ in a manner dependent on the NP properties. This relationship is sensitive to surface-solution interactions which are accurately captured with a combination of our self-consistent theories for PAA and Aβ. Surface modified NPs coupled with this robust and accurate molecular model represent a powerful platform to engineer nanotechnologies to modulate Aβ aggregation.