New Insight on pH‐Dependent Structural Switch of Aβ42 Trimers: Implications for Amyloid Nucleation and Pathogenesis

ABSTRACT Although Aβ42 trimers act as critical nucleating species in Alzheimer's disease (AD) amyloidogenesis, their structural dynamics and thermodynamic stability under fluctuating pH environments remain poorly defined. Here, we utilized pH‐replica exchange molecular dynamics (pH‐REMD) simulations to elucidate the conformational landscape of the full‐length Aβ42 trimer across a pH spectrum of 2–11. Our analyses demonstrate that β‐sheet propensity is highly pH‐dependent and non‐monotonic, peaking at ∼32% under neutral to mildly alkaline conditions (pH 7–9) before attenuating in extreme pH regimes. Furthermore, secondary structure assessments revealed a distinct topological transition: predominantly antiparallel β‐sheets at acidic pH (2–4) convert to parallel architectures at pH 5–6, whereas mixed topologies characterize the pH 7–9 regime. Binding free energy calculations confirmed that the trimer achieves maximum thermodynamic stability at pH 6, whereas highly acidic conditions (pH 2–5) thermodynamically favor dissociation. Mechanistically, the specific protonation states of histidine residues are associated with structural plasticity by modulating critical hydrogen‐bonding networks among the N‐terminus, central hydrophobic core, and C‐terminus. These findings elucidate the physicochemical principles governing Aβ42 trimer integrity, providing mechanistic insight into one determinant of early‐stage amyloid nucleation in AD, alongside other well‐established regulators such as peptide concentration and metal ions.