The Alzheimer’s Peptides Aβ40 and 42 Adopt Distinct Conformations in Water: A Combined MD / NMR Study

Abstract

SummaryThe role of two peptides, Aβ40 and Aβ42 in the early pathogenesis of the Alzheimer's disease (AD) is frequently emphasized in the literature. It is known that Aβ42 is more prone to aggregation than Aβ40, even though they only differ in two (IA) amino acid residues at the C-terminal end. A direct comparison of the ensembles of conformations adopted by the monomers in solution has been limited by the inherent flexibility of the unfolded peptides. Here we characterize the conformations of Aβ40 and Aβ42 in water by using a combination of molecular dynamics (MD) and measured scalar 3 J HNHα data from NMR experiments. We perform replica exchange MD (REMD) simulations and find that classical forcefields quantitatively reproduce the NMR data when the sampling is extended to the microseconds time scale. Using the quantitative agreement of the NMR data as a validation of the model, we proceed to compare the conformational ensembles of the Aβ40 and Aβ42 peptide monomers. Our analysis confirms the existence of structured regions within the otherwise flexible Aβ peptides. We find that the C-terminus of Aβ42 is more structured than that of Aβ40. The formation of a β-hairpin in the sequence 31 IIGLMVGGVVIA involving short strands at residues 31−34 and 38−41 reduces the C-terminal flexibility of the Aβ42 peptide and may be responsible for the higher propensity of this peptide to form amyloids. KeywordsAlzheimer's disease; Amyloid-β peptides; conformational ensemble; replica exchange molecular dynamics; J-coupling constants Two peptides have received tremendous interest in modern Alzheimer's disease (AD) research. Aβ40 and 42 are major products of the proteolytic cleavage of a multi-domain integral membrane type I protein, Amyloid-β Precursor Protein (APP), whose functions include cell adhesion, neuronal mobility and transcriptional regulation 1 . APP metabolism includes processing by a group of dedicated proteases, named secretases, in two known pathways to yield intracellular and extracellular fragments with a broad range of functions in synaptic transmission and neuronal plasticity 2 . During the amyloidogenic pathway, the action of β and subsequently γ secretase yields the Aβ peptides. The exact location of the transmembrane cleavage site for γ secretase results in a variability in the length of its Aβ product from 38 to 43 residues, however lengths of 40 and 42 are the dominant species. The physiological role of the Aβ peptides in vivo remains unclear. Aβ40 has been proposed to regulate the activity of K + channels 3 and also to modulate synaptic transmission 4 , however the mechanisms upon it * To whom correspondence should be addressed angel@rpi.edu Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final citable form. Please note that during the production p...

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

“…In agreement with previous experimental and theoretical studies, 15,[17][18][19]43 we detect that the β-sheet abundance in the C-terminal region of the wild-type Aβ42 is larger than that in the structures of the wild-type Aβ40 peptide. Surprisingly, we find that this trend is different in the structures of the E22Δ mutant-type Aβ40 and Aβ42 alloforms; the β-sheet abundance is larger in the C-terminal region of the E22Δ mutant-type Aβ40 rather than in its wild-type form.…”

“…The salt bridge between Asp23 and Lys28 is slightly more stable in the structures of Aβ40 rather than those of Aβ42, which is in agreement with previous studies. 15,17,43 Interestingly, this trend is inversed for the E22Δ mutant-type alloforms. We also calculated the salt bridge stability distribution between Asp23 and Lys28 (Figure 4) via comparing the distributions of the distances between the C γ (Asp23) and N ζ (Lys28) atoms.…”

“…Overall, the calculated secondary structure properties for the wild-type alloforms, for which experimental and theoretical data exist, are in excellent agreement with previously performed studies. [15][16][17][18]40,41 Figure 2 presents the free energy values for secondary structure transitions between two different secondary structure components per residue based on our free energy calculation method (see the Methods and Supporting Information for further details). Using these figures, we can identify which secondary structure component is most likely to result in the formation of a specific secondary structure of interest.…”

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

“…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.…”

“…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.…”