Modeling the Alzheimer Aβ17-42 Fibril Architecture: Tight Intermolecular Sheet-Sheet Association and Intramolecular Hydrated Cavities

Abstract

We investigate Abeta(17-42) protofibril structures in solution using molecular dynamics simulations. Recently, NMR and computations modeled the Abeta protofibril as a longitudinal stack of U-shaped molecules, creating an in-parallel beta-sheet and loop spine. Here we study the molecular architecture of the fibril formed by spine-spine association. We model in-register intermolecular beta-sheet-beta-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 Abeta 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 Abeta beta-strand-loop-beta-strand U-shaped motif creates a hydrophobic cavity with a diameter of 6-7 A, 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 Abeta 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.

Mechanisms and rates of nucleation of amyloid fibrils

“…This result suggested a steric zipper formed on the interface of two protofilaments 81 . Thus, the ∆ s value can be roughly estimated to be -22 k B T , the typical interaction free energy of a steric zipper 52 .…”

Oral Treatment with the d-Enantiomeric Peptide D3 Improves the Pathology and Behavior of Alzheimer’s Disease Transgenic Mice

“…All simulations and data analysis were performed using standard protocols as described previously (45). The calculation of the twist angle followed the work of Zheng et al (46). For the calculation of the twist angle, vectors between CR atoms of Val18 and Val24 were defined.…”

Annular Structures as Intermediates in Fibril Formation of Alzheimer Aβ17−42

“…For the linear-like morphology, we observe two stable organizations: (i) single-layered parallel-stranded β-sheet and (ii) double-layered parallel-stranded antiparallel β-sheets stacked perpendicular to the fibril axis exclusively through the hydrophobic CN-NC interface (data not shown). As for the Aβ linear-like structures, although the Aβ structure with the NC-CN interface is more energetically favorable and more stable than the Aβ structure with the CN-NC interface, Aβ structure with the CN-NC interface also displays high structural stability 33 . This indicates that Aβ peptides can be stacked on top of each other with the multiple layers in the lateral direction; that is, Aβ peptides can form multiple layers through either the NC-CN or the CN-NC interface.…”

“…We previously investigated Aβ linear-like protofibrils in solution using all-atom molecular dynamics (MD) simulations, particularly focusing on the effect of sheet-to-sheet interface on the preformed oligomers 33 . Our simulations suggested that double-layered Aβ oligomers stacked in antiparallel fashion and associated through the C-terminal-C-terminal (CC) interface perpendicular to the fibril axis were energetically more favorable than those with the Nterminal-N-terminal (NN) interface, although both interfaces exhibited structural stability.…”