Molecular dynamics simulations of Alzheimer Abeta40 elongation and lateral association.

Molecular dynamics simulations of Alzheimer Abeta40 elongation and lateral association. Research Abstract Details 

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Molecular dynamics simulations of Alzheimer Abeta40 elongation and lateral association. Abstract Text:

Amyloid-beta (Abeta) peptides can elongate in the fibril axis and associate in the lateral direction. We present detailed atomic Abeta models with different in-register intermolecular beta-sheet-beta-sheet associations. We probe structural stability, conformational dynamics, and association force of Abeta oligomers with various sizes and structures for both wild-type and mutated sequences using molecular dynamics (MD) simulations. MD simulations show that an Abeta oligomer that is laterally associated through the C-terminal-C-terminal interface is energetically more favorable than other oligomers with the N-terminal-N-terminal and C-terminal-N-terminal interfaces. We further develop a simple numerical model to describe the kinetics of Abeta aggregation process by considering fibril elongation and lateral association using a Monte Carlo algorithm. Kinetic data suggest that fibril elongation and lateral association are mutually competitive. Single-point mutations of Glu22 or Met35 at the interfaces have profound negative effects on intermolecular beta-sheet-beta-sheet association. These disease-related mutants (E22K, E22Q, and M35O) display more flexible structures, weaker lateral association, and stronger elongation tendencies than the wild type, suggesting that amyloid oligomerization and neurotoxicity might be linked to fibril longitudinal growth.

Molecular dynamics simulations of Alzheimer Abeta40 elongation and lateral association. Publishing Authors By Initials

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Molecular dynamics simulations of Alzheimer Abeta40 elongation and lateral association. Journal Published:

PUBLICATION TYPE: Journal Article

Journal: Frontiers in bioscience : a journal and virtual li

VOLUME: 13

Page Numbers: 3919-30

Journal Abbreviation: Front. Biosci.

ISSN: 1093-4715

DAY: 1

MONTH: 05

YEAR: 2008

Molecular dynamics simulations of Alzheimer Abeta40 elongation and lateral association. Information

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LANGUAGE: eng

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Grant and Affiliation Information for Molecular dynamics simulations of Alzheimer Abeta40 elongation and lateral association.

AFFILIATION: Department of Chemical and Biomolecular Engineering, The University of Akron, Akron, Ohio 44325.

Country: United States

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MEDLINETA: Front Biosci

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