Impact of Mutations on the Conformational Transition from α-Helix to β-Sheet Structures in Arctic-Type Aβ₄₀: Insights from Molecular Dynamics Simulations

Abstract

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 .

Helix-to-sheet transition of the Aβ42 peptide revealed using an enhanced sampling strategy and Markov state model

“…Therefore, the Aβ peptide must undergo a conformational transition from α-helix to intramolecular β-sheet before aggregation. As the essential step for Aβ aggregation, this conformational transition has also been the focus of extensive studies in recent years [25] , [26] , [27] , [28] . The investigation of conformational transitions can be helpful in probing the initial stages of aggregation and providing valuable structural insights into the inhibition of aggregation.…”

The F19W mutation reduces the binding affinity of the transmembrane Aβ11–40 trimer to the membrane bilayer

“…Mutations in the Ab peptide modify its toxicity, assembly, and rate of bril formation. Specically, the mutations in the CHC and loop regions, including F19W, 36 F20W, 36 L17A/F19A, 37 Flemish A21G, 38 Dutch E22Q, 39 Italian E22K, 40 Arctic E22G, 41,42 E22D, 43 and Iowa D23N 44 could affect the conformational changes in Ab oligomers. Another example shown that the combination of mutation A2V in N-terminal and histidine tautomerism can affect the Ab monomer structures and its aggregation process.…”