Modeling the Alzheimer A_17-42 Fibril Architecture: Tight Intermolecular Sheet-Sheet Association and Intramolecular Hydrated Cavities

¹ NCI-Frederick, SAIC-Frederick, Inc.
² SAIC Frederick, Inc

^* To whom correspondence should be addressed. E-mail: ruthn{at}ncifcrf.gov.

Submitted on April 13, 2007
Revised on June 1, 2007
Accepted on 6 July 2007

	Abstract

We investigate A_17-42 protofibril structures in solution using molecular dynamics simulations. Recently, NMR and computations modeled the A protofibril as a longitudinal stack of U-shaped molecules, creating an in-parallel -sheet and loop spine. Here we study the molecular architecture of the fibril formed by spine-spine association. We model in-register intermolecular -sheet--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 oligomers with different sheet-sheet interfaces. Double-layered oligomers associating through the C-terminal-C-terminal (CC) interface are energetically more favorable than those with the N-terminal-N-terminal (NN) interface, although both interfaces exhibit high structural stability. The CC interface is essentially stabilized by hydrophobic and van der Waals (shape-complementarity via M35-M35 contacts) intermolecular interactions, while the NN 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 -strand-loop--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 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.

Key Words: Abeta structure, aggregation, amyloid fibrils, amyloid motifs, fibril morphology, molecular dynamics simulations

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