A Hexamer of a Peptide Derived from Aβ<sub>16–36</sub> Adam G. Kreutzer Ryan K. Spencer Kate J. McKnelly Stan Yoo Imane L. Hamza Patrick J. Salveson James S. Nowick 10.1021/acs.biochem.7b00831.s001 https://acs.figshare.com/articles/journal_contribution/A_Hexamer_of_a_Peptide_Derived_from_A_sub_16_36_sub_/5545414 The absence of high-resolution structures of amyloid oligomers constitutes a major gap in our understanding of amyloid diseases. A growing body of evidence indicates that oligomers of the β-amyloid peptide Aβ are especially important in the progression of Alzheimer’s disease. In many Aβ oligomers, the Aβ monomer components are thought to adopt a β-hairpin conformation. This paper describes the design and study of a macrocyclic β-hairpin peptide derived from Aβ<sub>16–36</sub>. Sodium dodecyl sulfate–polyacrylamide gel electrophoresis and size exclusion chromatography studies show that the Aβ<sub>16–36</sub> β-hairpin peptide assembles in solution to form hexamers, trimers, and dimers. X-ray crystallography reveals that the peptide assembles to form a hexamer in the crystal state and that the hexamer is composed of dimers and trimers. Lactate dehydrogenase release assays show that the oligomers formed by the Aβ<sub>16–36</sub> β-hairpin peptide are toxic toward neuronally derived SH-SY5Y cells. Replica-exchange molecular dynamics demonstrates that the hexamer can accommodate full-length Aβ. These findings expand our understanding of the structure, solution-phase behavior, and biological activity of Aβ oligomers and may offer insights into the molecular basis of Alzheimer’s disease. 2017-10-13 00:00:00 macrocyclic β- hairpin peptide β- hairpin conformation dimers hexamer size exclusion chromatography studies show β oligomers Alzheimer SH-SY 5Y cells understanding trimer β monomer components β- amyloid peptide Lactate dehydrogenase release assays show