Partial Destabilization of Amyloid-β Protofibril by Methionine Photo-Oxidation: A Molecular Dynamic Simulation Study

Abstract

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.

Benzothiazole‐endoperoxide conjugates protect PC12 cells against β‐amyloid‐induced cell death via singlet oxygen mediated oxidative detoxification of fibrils

“…[16][17][18][19][20][21][22][23][24] Experiments with Aβ 1-42 peptide under the conditions photosensitized generation of singlet oxygen showed that the Met 35 is a major target for oxidation. [25,26] Interestingly, the oxidation of that particular side chain was previously shown to be an important conformational switch which stops the formation of the toxic oligomers and thus, reduces the overall toxicity Aβ. [27,28] While photogenerated singlet oxygen does serve as an important mechanistic tool, it does not have practical (clinical) potential, considering the highly impeded tissue penetration of light.…”

“…On the other hand, the photodynamic generation of singlet oxygen ( 1 O 2 ), was shown to degrade Aβ aggregates in vitro, and resulted in the remission of symptoms in disease models developed in C. elegans , Drosophila and mouse [16–24] . Experiments with Aβ 1–42 peptide under the conditions photosensitized generation of singlet oxygen showed that the Met 35 is a major target for oxidation [25,26] . Interestingly, the oxidation of that particular side chain was previously shown to be an important conformational switch which stops the formation of the toxic oligomers and thus, reduces the overall toxicity Aβ [27,28] .…”