Ruthenium(II) dipyridophenazine complexes have interesting photophysical properties, such as a light switching response in the presence of amyloid-β (Aβ) fibrils. Although molecular chirality plays an essential role in designing drugs with high specificity to biomolecule targets, including DNA and proteins, to our knowledge, there is no study focused on the interaction between the enantiomerically pure molecules and Aβ fibrils. In this project, we aim to elucidate the stereochemical effect in molecular binding processes with Aβ fibrils using racemic mixtures or enantiomerically pure [Ru(bpy)2(dppz)]2+ (bpy = 2,2’-bipyridine; dppz = dipyrido[3,2-a:2’,3’-c]phenazine). Binding assays were performed to determine the dissociation constant (Kd) and the binding stoichiometry (n; the number of Aβ monomers forming a single binding site for the Ru complex) of each [Ru(bpy)2(dppz)]2+ on Aβ fibrils. Additionally, circular dichroism (CD) spectra of Δ- and Λ-[Ru(bpy)2(dppz)]2+ in the presence of Aβ fibrils were measured to further characterize the binding interactions. In summary, the racemic and both Δ- and Λ-[Ru(bpy)2(dppz)]2+ showed similar Kd and n values on Aβ fibrils, and CD data indicated that the electronic transition changes observed in the presence of Aβ fibrils were the same for both enantiomers. Our data suggests that the binding mode of [Ru(bpy)2(dppz)]2+ enantiomers to Aβ fibrils is similar. Furthermore, salt titration studies were performed to gain further insight into the binding modes of [Ru(bpy)2(dppz)]2+ to Aβ fibrils. Analyzing the data using polyelectrolyte theory revealed the non-electrostatic contribution was approximately four times larger than the electrostatic contribution. Future work will be needed to establish the detailed binding modes of [Ru(bpy)2(dppz)]2+ enantiomers on Aβ fibrils, but these outcomes provide a significant step toward elucidating how to modulate the interactions between molecules and Aβ fibrils.

Exploring the interactions between ruthenium(II) dipyridophenazine enantiomers and amyloid-β fibrils

ACS Spring 2022

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