TiO Nanoparticles Catalyze Oxidation of Huntingtin Exon 1-Derived Peptides Impeding Aggregation: A Quantitative NMR Study of Binding and Kinetics.

Polyglutamine expansion within the N-terminal region of the huntingtin protein results in the formation of intracellular aggregates responsible for Huntington's disease, a fatal neurodegenerative condition. The interaction between TiO nanoparticles and huntingtin peptides comprising the N-terminal amphiphilic domain without (htt) or with (httQ) a ten-residue C-terminal polyglutamine tract, is investigated by NMR spectroscopy. TiO nanoparticles decrease aggregation of httQ by catalyzing the oxidation of Met to a sulfoxide, resulting in an aggregation-incompetent peptide. The oxidation agent is hydrogen peroxide generated on the surface of the TiO nanoparticles either by UV irradiation or at low steady-state levels in the dark. The binding kinetics of nonaggregating htt to TiO nanoparticles is characterized by quantitative analysis of N dark state exchange saturation transfer and lifetime line broadening NMR data. Binding involves a sparsely populated intermediate that experiences hindered rotational diffusion relative to the free state. Catalysis of methionine oxidation within the N-terminal domain of the huntingtin protein may potentially provide a strategy for delaying the onset of Huntington's disease.