pH-Dependent β-Strand Alignment of the Alzheimer's Amyloid-β (16-22) Peptide.

Abstract

The extracellular amyloid plaques of amyloid-β (Aβ) peptides formed in the human brain are an important pathological hallmark of Alzheimer's disease. There is evidence that pH affects the morphologies of fibrils and the kinetics of amyloid fibril formation. However, the underlying molecular mechanism is not well understood. In this study, as a first step to understand pH-modulated Aβ fibril formation, we investigated the conformations of Aβ (16-22) octamers by performing extensive all-atom replica exchange molecular dynamics simulations at both neutral and acidic pH. Our simulations showed that the residues Phe20 and Ala21 in the C terminal have higher β-sheet probability (78.8%, 55.8%) at acidic pH than (62.3%, 43.6%) at neutral pH. Out-of-register antiparallel β-strand alignments of the Aβ (16-22) peptide are predominantly in the 1-, 2-, and 3-residue shifts at both pH conditions, which agrees well with solid-state NMR results on Aβ peptides. We also found that there are multiple in-register and out-of-register parallel β-strand alignments under both pH conditions. However, the pH conditions affect the probability of β-strand alignments for the Aβ (16-22) peptide, and the residue-residue interaction of bilayer β-sheet and β-barrel are different at different pH conditions. Our analysis showed that the electrostatic interactions among peptides are much stronger at neutral pH than at acidic pH, while the vdW interactions are slightly stronger at acidic pH than at neutral pH. These results provide atomistic insight into the early stage of aggregation of amyloid-β (Aβ) peptides at acidic and neutral pH conditions.