|Title||Tetrameric Aβ40 and Aβ42 β-Barrel Structures by Extensive Atomistic Simulations. I. In a Bilayer Mimicking a Neuronal Membrane.|
|Publication Type||Journal Article|
|Year of Publication||2019|
|Authors||Nguyen PHoang, Campanera JM, Ngo STung, Loquet A, Derreumaux P|
|Journal||J Phys Chem B|
|Date Published||2019 May 02|
The amyloid-β (Aβ) 42 oligomers are much more toxic than Aβ40 oligomers in Alzheimer's disease. Numerous experiments indicate that toxicity could involve the formation of pores in membranes, but experimental high-resolution structure determination of these pore-forming Aβ oligomers has been impeded by aggregate heterogeneity. Using extensive atomistic simulations, low-resolution data obtained in lipid bilayers, and other theoretical factors, we proposed atomic structures of Aβ40 and Aβ42 β-barrels in a bilayer mimicking a neuronal membrane. The 3D model, which consists of tetramer subunits, two distinct β-hairpin motifs and an asymmetric arrangement of eight antiparallel β-strands, is drastically destabilized for Aβ40 compared to its Aβ42 counterpart. Our computational modeling has several implications in Alzheimer's disease, sheds light on the amyloid pore hypothesis, and explains the higher deleterious property of Aβ42.
|Alternate Journal||J Phys Chem B|