Role of the familial Dutch mutation E22Q in the folding and aggregation of the 15–28 fragment of the Alzheimer amyloid-β protein

Amyloid fibrils, large ordered aggregates of amyloid β proteins (Aβ), are clinical hallmarks of Alzheimer's disease (AD). The aggregation properties of amyloid β proteins can be strongly affected by single-point mutations at positions 22 and 23. The Dutch mutation involves a substitution at position 22 (E22Q) and leads to increased deposition rates of the AβE22Q peptide onto preseeded fibrils. We investigate the effect of the E22Q mutation on two key regions involved in the folding and aggregation of the Aβ peptide through replica exchange molecular dynamics simulations of the 15–28 fragment of the Aβ peptide. The Aβ15–28 peptide encompasses the 22–28 region that constitutes the most structured part of the Aβ peptide (the E22–K28 bend), as well as the central hydrophobic cluster (CHC) (segment 17–21), the primary docking site for Aβ monomers depositing onto fibrils. Our simulations show that the 22–28 bend is preserved in the Aβ(15–28) peptide and that the CHC, which is mostly unstructured, interacts with this bend region. The E22Q mutation does not affect the structure of the bend but weakens the interactions between the CHC and the bend. This leads to an increased population of β-structure in the CHC. Our analysis of the fibril elongation reaction reveals that the CHC adopts a β-strand conformation in the transition state ensemble, and that the E22Q mutation increases aggregation rates by lowering the barrier for Aβ monomer deposition onto a fibril. Thermodynamic signatures of this enhanced fibrillization process from our simulations are in good agreement with experimental observations.