This Article Full Text Full Text (PDF) All Versions of this Article: biophysj.107.110700v1 93/9/3046    most recent Alert me when this article is cited Alert me if a correction is posted Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Zheng, J. Articles by Nussinov, R. Search for Related Content PubMed PubMed Citation Articles by Zheng, J. Articles by Nussinov, R.

Modeling the Alzheimer Aβ_17-42 Fibril Architecture: Tight Intermolecular Sheet-Sheet Association and Intramolecular Hydrated Cavities

Jie Zheng ^*, Hyunbum Jang ^*, Buyong Ma ^*, Chung-Jun Tsai ^* and Ruth Nussinov ^* 

^* Basic Research Program, SAIC-Frederick Center for Cancer Research, Nanobiology Program, NCI-Frederick, Frederick, Maryland 21702; and Sackler Institute of Molecular Medicine, Department of Human Molecular Genetics and Biochemistry, Sackler School of Medicine, Tel Aviv University, Tel Aviv, Israel

Correspondence: Address reprint requests to Ruth Nussinov, E-mail: ruthn{at}ncifcrf.gov.

We investigate Aβ_17-42 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.

This article has been cited by other articles:

				T. Yamazaki, N. Blinov, D. Wishart, and A. Kovalenko Hydration Effects on the HET-s Prion and Amyloid-{beta} Fibrillous Aggregates, Studied with Three-Dimensional Molecular Theory of Solvation Biophys. J., November 15, 2008; 95(10): 4540 - 4548. [Abstract] [Full Text] [PDF]

				A. De Simone, L. Esposito, C. Pedone, and L. Vitagliano Insights into Stability and Toxicity of Amyloid-Like Oligomers by Replica Exchange Molecular Dynamics Analyses Biophys. J., August 15, 2008; 95(4): 1965 - 1973. [Abstract] [Full Text] [PDF]

				N. L. Fawzi, K. L. Kohlstedt, Y. Okabe, and T. Head-Gordon Protofibril Assemblies of the Arctic, Dutch, and Flemish Mutants of the Alzheimer's A{beta}1-40 Peptide Biophys. J., March 15, 2008; 94(6): 2007 - 2016. [Abstract] [Full Text] [PDF]