Nix, Andrew J.

Synchrotron based hydroxyl radical footprinting (HRF) was employed to study the formation of Aβ 42 oligomers, believed to be the neurotoxic species in Alzheimer's disease. Rates of oxidative modification for seventeen individual residues (F4, Y10, H13, H14, L17, F19, F20, V24, K28, I31, I32, M35, V36, V39, V40, I41) were determined for monomer, 2‐4mer, and oligomer Aβ 42 relative to intrinsic rates of modification determined for the same residues in fragment peptide. The ratio of measured and intrinsic rates reveals protection from hydroxyl radical attack due to reduced side chain solvent accessibility for structured Aβ 42 . Protection observed in the intrinsically disordered Aβ 42 monomer is consistent with transient C‐terminal β‐strand formation and partial folding in the hydrophobic core region. Our results also reveal dimerization (and further assembly) contacts that are consistent both with oligomer C‐terminal antiparallel β‐sheet formation previously indicated from published solid state NMR work studies and newly detected N‐terminal structure.