pH-dependent conformational ensemble and polymorphism of amyloid-β core fragment

Characterization of amyloid oligomeric species is important due to its possible responsibility for the toxicity of amyloid proteins, whereas it is difficult to detect by current spectroscopic techniques. The pH-dependent tetramerization and fibrillation of the central hydrophobic segment of Alzheimer amyloid β-peptide (Aβ(12-24)) were respectively explored by all-atom replica exchange molecular dynamics simulations and by fluorescence and atomic force microscopy measurements. Our combined study shows that more β-sheet structures in the early event of tetramerization is linked directly to the high propensity to form amyloid fibrils in the consequent fibrillation. Both tetramerization and fibrillation are strongly regulated by pH. At pH 5.0, Aβ(12-24) has two opposite terminal charges. The electrostatic attraction between the side-chains of His13/His14 and Glu22/Asp23 thus acts as a "pattern keeper", resulting in high propensity of amyloid formation. These results suggest that pH effects most likely by affecting the ionization properties of the Aβ(12-24) peptide. Specifically, the pH-dependent equilibrium conformational distribution of different aggregate species are well-investigated in detail. Our findings also give hints to other experimental findings that the kinetics and morphologies of Aβ fibril formation are strongly pH-dependent.