Selective photosensitized oxidation of amyloid protein aggregates is being investigated as a possible therapeutic strategy for treating Alzheimer's disease (AD). Photo-oxidation has been shown to degrade amyloid-β (Aβ) aggregates and ameliorate aggregate toxicity in vitro and reduce aggregate levels in the brains of AD animal models. To shed light on the mechanism by which photo-oxidation induces fibril destabilization, we carried out an all-atom molecular dynamics (MD) simulation to examine the effect of methionine (Met35) oxidation on the conformation and stability of a β-sheet-rich Aβ9-40 protofibril. Analyses of up to 1 μs simulations showed that the oxidation of the Met35 residues, which resulted in the addition of hydrophilic oxygens in the fibril core, reduced the overall conformational stability of the protofibril. Specifically, Met35 disrupted the hydrophobic interface that stabilizes the stacking of the two hexamers that comprise the protofibril. The oxidized protofibril is more solvent exposed and exhibits more backbone flexibility. However, the protofibril retained the underlying U-shaped architecture of each peptide upon oxidation, and although some loss of β-sheets occurred, a significant portion remained. Our simulation results are thus consistent with our experimental observation that photo-oxidation of Aβ40 fibril resulted in the dis-agglomeration and fragmentation of Aβ fibrils but did not cause complete disruption of the fibrillar morphology or β-sheet structures. The partial destabilization of Aβ aggregates supports the further development of photosensitized platforms for the targeting and clearing of Aβ aggregates as a therapeutic strategy for treating AD.
© 2023 The Authors. Published by American Chemical Society.