Aβ under stress: the effects of acidosis, Cu²⁺-binding, and oxidation on amyloid β-peptide dimers

In light of the high affinity of Cu²⁺ for Alzheimer's Aβ_1–42 and its ability to subsequently catalyze the formation of radicals, we examine the effects of Cu²⁺ binding, Aβ oxidation, and an acidic environment on the conformational dynamics of the smallest Aβ_1–42 oligomer, the Aβ_1–42 dimer. Transition networks calculated from Hamiltonian replica exchange molecular dynamics (H-REMD) simulations reveal that the decreased pH considerably increased the β-sheet content, whereas Cu²⁺ binding increased the exposed hydrophobic surface area, both of which can contribute to an increased oligomerization propensity and toxicity.