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.

Arginine and Disordered Amyloid-β Peptide Structures: Molecular Level Insights into the Toxicity in Alzheimer’s Disease

“…It is also interesting to note that the tertiary structures of the R5A mutant-type peptide in the most favorable PMF basin ( Figure 5A) more closely resemble those of the wild-type Aβ42 structures of the least favorable PMF basin. 5,6 Overall, these results indicate that the presence of R increases the formation of intramolecular interactions that result in thermodynamically more preferred structures. In other words, R, which is a residue generally known as a disorder promoting polar residue, largely causes specific structuring in the disordered peptide conformations in terms of intramolecular long-range interactions.…”

“…In addition, the abundant β-sheet structure formation in the C-terminal region of the wild-type Aβ42 peptide has been linked to the aggregation mechanism. 5,6,18,19 Furthermore, the stabilization of the turn conformation at A21−A30 in the wild-type Aβ42 peptide has been associated with the formation of salt bridges and hydrophobic interactions. 5,6,19 Interestingly, prominent β-sheet structure is formed at R5 located in the N-terminal region of Aβ42, and this residue forms also various stable intramolecular interactions with other residues of the peptide located in the N-and C-terminal or mid-domain (L17−G29) regions in an aqueous solution environment.…”

“…5,6,18,19 Furthermore, the stabilization of the turn conformation at A21−A30 in the wild-type Aβ42 peptide has been associated with the formation of salt bridges and hydrophobic interactions. 5,6,19 Interestingly, prominent β-sheet structure is formed at R5 located in the N-terminal region of Aβ42, and this residue forms also various stable intramolecular interactions with other residues of the peptide located in the N-and C-terminal or mid-domain (L17−G29) regions in an aqueous solution environment. 5,6 Experimental R5A mutation studies showed a decrease both in the tendency toward Aβ aggregate formation and a reduced toxicity related to Alzheimer's disease.…”

“…4−6,17−20,22,24,32−37 For example, α-helix and β-sheet structure formations, which have been directly related to the toxicity of Aβ, have been detected in various regions of the disordered Aβ42 peptide at the atomic level using computational and theoretical tools. 5,6,[17][18][19][20]24 We recently developed a theoretical strategy that calculates the secondary structure transition stabilities per residue in the structures of disordered proteins, which has been successfully applied on wild-and genetic mutant-type disordered proteins at the center of Alzheimer's and Parkinson's diseases as well as type II diabetes. 6−8 For gaining insights into the role of R and for providing detailed knowledge about the impact of R5A mutation on the structures and thermodynamic properties of the wild-type Aβ42 peptide, we performed extensive parallel tempering molecular dynamics simulations along with special sampling techniques.…”

Structures and Free Energy Landscapes of the Wild-Type and A30P Mutant-Type α-Synuclein Proteins with Dynamics

“…39,40 The free energy values identify which secondary structure transitions are most preferred and thus can be used to identify which structures are most likely to precede the formation of secondary structure components of interest. These calculations show turn or helix to coil transitions as well as helix to turn or turn to helix transitions are overall the most preferred secondary structure transitions for both the wild-type and A30P mutant-type αS proteins in an aqueous solution environment.…”