Modeling the Alzheimer Abeta17-42 fibril architecture: tight intermolecular sheet-sheet association and intramolecular hydrated cavities.

Modeling the Alzheimer Abeta17-42 fibril architecture: tight intermolecular sheet-sheet association and intramolecular hydrated cavities. Research Abstract Details 

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Modeling the Alzheimer Abeta17-42 fibril architecture: tight intermolecular sheet-sheet association and intramolecular hydrated cavities. Abstract Text:

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

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.

Modeling the Alzheimer Abeta17-42 fibril architecture: tight intermolecular sheet-sheet association and intramolecular hydrated cavities. Publishing Authors By Initials

J Zheng,H Jang,B Ma,CJ Tsai,R Nussinov,J Zheng,H Jang,B Ma,CJ Tsai,R Nussinov,

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Modeling the Alzheimer Abeta17-42 fibril architecture: tight intermolecular sheet-sheet association and intramolecular hydrated cavities. Journal Published:

PUBLICATION TYPE: Research Support, N.I.H., Intr

Journal: Biophysical journal

VOLUME: 93

Page Numbers: 3046-57

Journal Abbreviation: Biophys. J.

ISSN: 0006-3495

DAY: 3

MONTH: 08

YEAR: 2007

Modeling the Alzheimer Abeta17-42 fibril architecture: tight intermolecular sheet-sheet association and intramolecular hydrated cavities. Information

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LANGUAGE: eng

NlmUniqueID: 370626

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Grant and Affiliation Information for Modeling the Alzheimer Abeta17-42 fibril architecture: tight intermolecular sheet-sheet association and intramolecular hydrated cavities.

AFFILIATION: Basic Research Program, SAIC-Frederick Center for Cancer Research, Nanobiology Program, NCI-Frederick, Frederick, Maryland 21702, USA.

Country: United States

AGENCY: United States NCI

GRANT: N01-CO-12400

ACRONYM: CO

MEDLINETA: Biophys J

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