Modeling the Alzheimer A β17-42 Fibril Architecture: Tight Intermolecular Sheet-Sheet Association and Intramolecular Hydrated Cavities

Abstract

We investigate A β 17-42 protofibril structures in solution using molecular dynamics simulations. Recently, NMR and computations modeled the A β 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 A β 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 A β 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 A β 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.