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

Intrinsically disordered peptides, such as amyloid beta 42 (A beta 42), lack a well-defined structure in solution. A beta 42 can undergo abnormal aggregation and amyloidogenesis in the brain, forming fibrilar plaques, a hallmark of Alzheimer's disease. The insoluble fibrillar forms of A beta 42 exhibit well-defined, cross beta-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 A beta 42 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 A beta 42 are known to exhibit helical propensity in different physiological conditions. NMR spectroscopy has shown that the A beta 42 monomer at lower pH can adopt an alpha-helical conformation and as the pH is increased, the peptide switches to beta-sheet conformation and aggregation occurs. CD spectroscopy studies of aggregation have shown the presence of an initial spike in the amount of alpha-helical content at the start of aggregation. Such an increase in alpha-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 A beta 42 in solution to identify molecular properties that may mediate the early stages of oligomerization. We hypothesized that conformations with alpha-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, alpha-helical conformations are thermodynamically accessible, more so than beta-sheet conformations. Importantly, for the first time alpha-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 A beta 42.

Automated summary

Intrinsically disordered peptide A beta 42 is associated with formation of amyloid plaques and Alzheimer's disease. The mechanism of oligomerization of A beta 42 is not well understood due to its structural disorder. Molecular dynamics simulations reveal that A beta 42 conformations with alpha-helical structure have a higher probability of initiating aggregation, shedding light on the mechanism of oligomerization of this disordered peptide.