The Structures of the E22Δ Mutant-Type Amyloid-β Alloforms and the Impact of E22Δ Mutation on the Structures of the Wild-Type Amyloid-β Alloforms

Abstract

Structural differences between the intrinsically disordered fibrillogenic wild-type Aβ40 and Aβ42 peptides are linked to Alzheimer's disease. Recently, the E22Δ genetic missense mutation was detected in patients exhibiting Alzheimer's-disease type dementia. However, detailed knowledge about the E22Δ mutant-type Aβ40 and Aβ42 alloform structures as well as the differences from the wild-type Aβ40 and Aβ42 alloform structures is currently lacking. In this study, we present the structures of the E22Δ mutant-type Aβ40 and Aβ42 alloforms as well as the impact of E22Δ mutation on the wild-type Aβ40 and Aβ42 alloform structures. For this purpose, we performed extensive microsecond-time scale parallel tempering molecular dynamics simulations coupled with thermodynamic calculations. For studying the residual secondary structure component transition stabilities, we developed and applied a new theoretical strategy in our studies. We find that the E22Δ mutant-type Aβ40 might have a higher tendency toward aggregation due to more abundant β-sheet formation in the C-terminal region in comparison to the E22Δ mutant-type Aβ42 peptide. More abundant α-helix is formed in the mid-domain regions of the E22Δ mutant-type Aβ alloforms rather than in their wild-type forms. The turn structure at Ala21-Ala30 of the wild-type Aβ, which has been linked to the aggregation process, is less abundant upon E22Δ mutation of both Aβ alloforms. Intramolecular interactions between the N-terminal and central hydrophobic core (CHC), N- and C-terminal, and CHC and C-terminal regions are less abundant or disappear in the E22Δ mutant-type Aβ alloform structures. The thermodynamic trends indicate that the wild-type Aβ42 tends to aggregate more than the wild-type Aβ40 peptide, which is in agreement with experiments. However, this trend is vice versa for the E22Δ mutant-type alloforms. The structural properties of the E22Δ mutant-type Aβ40 and Aβ42 peptides reported herein may prove useful for the development of new drugs to block the formation of toxic E22Δ mutant-type oligomers by either stabilizing helical or destabilizing β-sheet structure in the C-terminal region of these two mutant alloforms.