Structures of β-Amyloid Peptide 1−40, 1−42, and 1−55—the 672−726 Fragment of APP—in a Membrane Environment with Implications for Interactions with γ-Secretase

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Abstract
Aggregation of Amyloid β (Aβ) peptide has been linked to the neurodegenerative Alzheimer’s Disease and implicated in other amyloid diseases including cerebral amyloid angiopathy. Aβ peptide is generated by cleavage of the amyloid precursor protein (APP) by transmembrane proteases. It is crucial to determine the structures of β-amyloid peptides in a membrane to provide a molecular basis for the cleavage mechanism. We report the structures of amyloid β peptide (Aβ1−40 and Aβ1−42) as well as the 672−726 fragment of APP (referred to as Aβ1−55) in a membrane environment determined by replica-exchange molecular dynamics simulation. Aβ1−40 is found to have two helical domains A (13−22) and B(30−35) and a type I β-turn at 23−27. The peptide is localized at the interface between membrane and solvent. Substantial fluctuations in domain A are observed. The dominant simulated tertiary structure of Aβ1−40 is observed to be similar to the simulated Aβ1−42 structure. However, there are differences observed in the overall conformational ensemble, as characterized by the two-dimensional free energy surfaces. The fragment of APP (Aβ1−55) is observed to have a long transmembrane helix. The position of the transmembrane region and ensemble of membrane structures are elucidated. The conformational transition between the transmembrane Aβ1−55 structure, prior to cleavage, and the Aβ1−40 structure, following cleavage, is proposed.