Structure and Dynamics of Lipid‐Stabilized Amyloid Beta Aβ 1–42 Oligomers

ABSTRACT The Aβ peptide contributes to Alzheimer's disease through various mechanisms, including cell membrane disruption. While the fibrillar structure of Aβ 1–42 in aqueous medium has been elucidated, its oligomer structure remains elusive. We have combined Fourier transform infrared (FTIR) spectroscopy, transmission electron microscopy (TEM), solid‐state NMR (ssNMR), and molecular dynamics (MD) approaches to achieve a structural model for Aβ 1–42 octamer in lipid bilayers. FTIR data identify conformational transitions of Aβ 1–42 to a stable β‐sheet structure. ssNMR analysis allows assignment of 38 out of 42 Aβ 1–42 residues, with three additional inter‐residue contacts to define the tertiary fold. Combined, MD simulations produce a structural model of Aβ 1–42 octamers in a novel sushi‐roll fold of in‐register cross‐β motif with a lipid‐filled internal cavity. The membrane‐embedded structure of Aβ 1–42 and the mode of peptide‐lipid interactions provide a better understanding of Aβ neurotoxicity.