Impact of Mutations on the Conformational Transition from α-Helix to β-Sheet Structures in Arctic-Type Aβ(40): Insights from Molecular Dynamics Simulations

[Image: see text] The amyloid-β (Aβ) protein aggregation into toxic oligomers and fibrils has been recognized as a key player in the pathogenesis of Alzheimer’s disease. Recent experiments reported that a double alanine mutation (L17A/F19A) in the central hydrophobic core (CHC) region of [G22]Aβ(40) (familial Arctic mutation) diminished the self-assembly propensity of [G22]Aβ(40). However, the molecular mechanism behind the decreased aggregation tendency of [A17/A19/G22]Aβ(40) is not well understood. Herein, we carried out molecular dynamics simulations to elucidate the structure and dynamics of [G22]Aβ(40) and [A17/A19/G22]Aβ(40). The results for the secondary structure analysis reveal a significantly increased amount of the helical content in the CHC and C-terminal region of [A17/A19/G22]Aβ(40) as compared to [G22]Aβ(40). The bending free-energy analysis of D23–K28 salt bridge suggests that the double alanine mutation in the CHC region of [G22]Aβ(40) has the potential to reduce the fibril formation rate by 0.57 times of [G22]Aβ(40). Unlike [G22]Aβ(40), [A17/A19/G22]Aβ(40) largely sampled helical conformation, as determined by the minimum energy conformations extracted from the free-energy landscape. The present study provided atomic level details into the experimentally observed diminished aggregation tendency of [A17/A19/G22]Aβ(40) as compared to [G22]Aβ(40).