버전 1.1

Deposition of amyloid-β (Aβ) proteins is the conventional pathological hallmark of Alzhemer’s disease(AD). The Aβ protein formed from the amyloid precursor protein is predominated by the 40 residue protein (Aβ40) and by the 42 residue protein (Aβ42). While Aβ40 and Aβ42 differ in only two amino acid residues at the C-terminal end, Aβ42 is much more prone to aggregate and exhibits more neurotoxicity than Aβ40. Here, we investigate the molecular origin of the difference in he aggregation propensity of these two proteins by performing fully atomistic, explicit-water molecular dynamics simulation. Then, it is followed by the solvation thermodynamic analysis based on the integral-equation theory of liquids. We find that Aβ42 displays higher tendency to adopt β-sheet conformation than Aβ40, which would consequently facilitate the conversion to the β-sheet rich fibril structure. Furthermore, the solvation thermodynamic analysis on the simulated protein conformations indicates that Aβ42 is more hydrophobic than Aβ40, implying that the surrounding water imparts a larger thermodynamic driving force for the self-assembly of Aβ42. Taken together, our results provide structural and thermodynamic grounds on why Aβ42 is more aggregation-prone than Aβ40 is aqueous environments.

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