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 Alzheimers disease (AD). Photo-oxidation has been shown to lead to the degradation of amyloid-{beta} (A{beta}) aggregates, ameliorate aggregate toxicity 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 highly {beta}-sheet-rich A{beta}9-40 protofibril composed of 12 monomers. Analyses of up to 1 s MD simulations showed that the oxidation of the Met35 residues reduced the overall conformational stability of the protofibril. Specifically, Met35 oxidation that resulted in the addition of hydrophilic oxygens disrupted the hydrophobic interface that stabilizes the stacking of the two hexamers that composed the protofibril. The oxidized protofibril is more solvent exposed, less compact, and exhibits more backbone flexibility. However, it retained the underlying U-shaped architecture of each peptide. Although some loss of {beta}-sheets occurred, a significant portion (~76%) remained. twisting of the peptides along the protofibril axis was observed, and the hexamers remained. Our simulation results are thus consistent with our experimental observation that photo-oxidation of A{beta}40 fibrils results in the dis-agglomeration and fragmentation of A{beta} fibrils, but did not cause complete disruption of the fibrillar morphology or {beta}-sheet structures. The partial destabilization of A{beta} aggregates supports the further development of photosensitized platforms for the selective targeting and clearance of A{beta} aggregates as a therapeutic strategy for treating AD.