Modeling the Alzheimer Ab17-42 Fibril Architecture: Tight Intermolecular Sheet-sheet Association and Intramolecular Hydrated Cavities

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Fall 2007


We investigate Aβ17-42 protofibril structures in solution using molecular dynamics simulations. Recently, NMR and computations modeled the Aβ protofibril as a longitudinal stack of U-shaped molecules, creating an in-parallel β-sheet and loop spine. Here we study the molecular architecture of the fibril formed by spine-spine association. We model in-register intermolecular β-sheet–β-sheet associations and study the consequences of Alzheimer's mutations (E22G, E22Q, E22K, and M35A) on the organization. We assess the structural stability and association force of Aβ oligomers with different sheet-sheet interfaces. Double-layered oligomers associating through the C-terminal–C-terminal interface are energetically more favorable than those with the N-terminal–N-terminal interface, although both interfaces exhibit high structural stability. The C-terminal–C-terminal interface is essentially stabilized by hydrophobic and van der Waals (shape complementarity via M35-M35 contacts) intermolecular interactions, whereas the N-terminal–N-terminal interface is stabilized by hydrophobic and electrostatic interactions. Hence, shape complementarity, or the “steric zipper” motif plays an important role in amyloid formation. On the other hand, the intramolecular Aβ β-strand-loop-β-strand U-shaped motif creates a hydrophobic cavity with a diameter of 6–7 Å, allowing water molecules and ions to conduct through. The hydrated hydrophobic cavities may allow optimization of the sheet association and constitute a typical feature of fibrils, in addition to the tight sheet-sheet association. Thus, we propose that Aβ fiber architecture consists of alternating layers of tight packing and hydrated cavities running along the fibrillar axis, which might be possibly detected by high-resolution imaging.





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