Characterization of the Conformations of Amyloid Beta 42 in Solution That May Mediate Its Initial Hydrophobic Aggregation

Abstract

Intrinsically disordered peptides, such as amyloid β42 (Aβ42), lack a welldefined structure in solution. Aβ42 can undergo abnormal aggregation and amyloidogenesis in the brain, forming fibrillar plaques, a hallmark of Alzheimer's disease. The insoluble fibrillar forms of Aβ42 exhibit well-defined, cross β-sheet structures at the molecular level and are less toxic than the soluble, intermediate disordered oligomeric forms. However, the mechanism of initial interaction of monomers and subsequent oligomerization is not well understood. The structural disorder of Aβ42 adds to the challenges of determining the structural properties of its monomers, making it difficult to understand the underlying molecular mechanism of pathogenic aggregation. Certain regions of Aβ42 are known to exhibit helical propensity in different physiological conditions. NMR spectroscopy has shown that the Aβ42 monomer at lower pH can adopt an α-helical conformation and as the pH is increased, the peptide switches to β-sheet conformation and aggregation occurs. CD spectroscopy studies of aggregation have shown the presence of an initial spike in the amount of α-helical content at the start of aggregation. Such an increase in α-helical content suggests a mechanism wherein the peptide can expose critical non-polar residues for interaction, leading to hydrophobic aggregation with other interacting peptides. We have used molecular dynamics simulations to characterize in detail the conformational landscape of monomeric Aβ42 in solution to identify molecular properties that may mediate the early stages of oligomerization. We hypothesized that conformations with α-helical structure have a higher probability of initiating aggregation because they increase the hydrophobicity of the peptide. Although random coil conformations were found to be the most dominant, as expected, α-helical conformations are thermodynamically accessible, more so than β-sheet conformations. Importantly, for the first time α-helical conformations are observed to increase the exposure of aromatic and hydrophobic residues to the aqueous solvent, favoring their hydrophobically driven interaction with other monomers to initiate aggregation. These findings constitute a first step toward characterizing the mechanism of formation of disordered, low-order oligomers of Aβ42.

Influence of force field choice on the conformational landscape of rat and human islet amyloid polypeptide

“…METAGUI calculates the free energy for each microstate, and the following formula can be applied to each observable property postconvergence. Where the sum is across all the microstates and O α is the arithmetic average of the observable property across all configurations within microstate α 55 . This approach computed average chemical shifts and secondary structure properties using in‐house scripts 58 …”

“… 55 This approach computed average chemical shifts and secondary structure properties using in‐house scripts. 58 …”

Mutexa: A Computational Ecosystem for Intelligent Protein Engineering

“…This descriptor has been defined to be the substrate-positioning index (SPI) in our later study . The form of SPI is similar to the definition of hydrophobicity index …”

“…63 The form of SPI is similar to the definition of hydrophobicity index. 143 We further investigated the distribution of ΔG ‡ values versus SPI for C10 and C12 substrates combined with different enzyme variants. The distribution conforms to a two-segment, piecewise linear correlation plot with a volcano shape (Figure 5d).…”

Metastable Alpha-rich and Beta-rich Conformations of Small Aβ42 Peptide Oligomers

“…78 Computationally, AlphaFold2 α-helical tetramer and hexamer structures are very stable using CHARMM36m-TIP3P modified and AMBER99SB-DISP for 0.3 μs MD simulations at 310 K. 54 Transient formation of helical conformations differing from helix bundles was reported by numerous simulations of Aβ40 and Aβ42 oligomers, 7,28,46,79 but a recent simulation proposed that conformations with α-helical structure have a high propensity to initiate Aβ42 aggregation. 80 Finally, it should be noted that the helix propensity of amyloid peptides is a fundamental requirement to fulfill the lipid-chaperon model, 81 and helical intermediates during amyloid formation are catalysed by membranes. 36,72…”