Using chiral peptide substitutions to probe the structure function relationship of a key residue of Aβ42

Amyloid beta‐protein 42 plays an important role in the onset and progression of Alzheimer's disease. Familial mutations have identified the glutamate residue 22 as a hotspot with regard to peptide neurotoxicity. We introduce an approach to study the influence of systematic sidechain modification at this residue, employing chirality as a structural probe. Circular dichroism experiments reveal that charge‐preserving alterations of the amino acid sidechain attenuate the characteristic random coil to β‐sheet transition associated with the wildtype peptide. Removal of the negative charge from residue 22, a trait observed with all known familial mutations at this residue, gives rise to a peptide with limited random coil propensity and high β‐sheet characteristics. Our approach can be extended to other residues of Aβ, as well as further amyloidogenic peptides.