An N-terminal acidic β-sheet domain is responsible for the metal-accumulation properties of amyloid-β protofibrils: a molecular dynamics study.

Abstract

The influence of metal ions on the structure of amyloid- $\beta$ (Aβ) protofibril models was studied through molecular dynamics to explore the molecular mechanisms underlying metal-induced Aβ aggregation relevant in Alzheimer's disease (AD). The models included 36-, 48-, and 188-mers of the Aβ₄₂ sequence and two disease-modifying variants. Primary structural effects were observed at the N-terminal domain, as it became susceptible to the presence of cations. Specially when β-sheets predominate, this motif orients N-terminal acidic residues toward one single face of the β-sheet, resulting in the formation of an acidic region that attracts cations from the media and promotes the folding of the N-terminal region, with implications in amyloid aggregation. The molecular phenotype of the protofibril models based on Aβ variants shows that the AD-causative D7N mutation promotes the formation of N-terminal β-sheets and accumulates more Zn²⁺, in contrast to the non-amyloidogenic rodent sequence that hinders the β-sheets and is more selective for Na⁺ over Zn²⁺ cations. It is proposed that forming an acidic β-sheet domain and accumulating cations is a plausible molecular mechanism connecting the elevated affinity and concentration of metals in Aβ fibrils to their high content of β-sheet structure at the N-terminal sequence.