IMR Press / FBL / Volume 13 / Issue 10 / DOI: 10.2741/2980

Frontiers in Bioscience-Landmark (FBL) is published by IMR Press from Volume 26 Issue 5 (2021). Previous articles were published by another publisher on a subscription basis, and they are hosted by IMR Press on imrpress.com as a courtesy and upon agreement with Frontiers in Bioscience.

Open Access Article

Molecular dynamics simulations of Alzheimer Aβ40 elongation and lateral association

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1 Department of Chemical and Biomolecular Engineering, The University of Akron, Akron, Ohio 44325
2 Basic Research Program, SAIC-Frederick, Inc., Center for Cancer Research Nanobiology Program, NCI-Frederick, Frederick, MD 21702
3 Research and Development Center for Membrane Technology and Department of Chemical Engineering, Chung Yuan Christian University, Jhong-Li, Taoyuan 320, Republic of China
4 Sackler Institute of Molecular Medicine, Department of Human Genetics and Molecular Medicine, Sackler School of Medicine, Tel Aviv University, Tel Aviv 69978, Israel

*Author to whom correspondence should be addressed.

Academic Editor: Buyong Ma

Front. Biosci. (Landmark Ed) 2008, 13(10), 3919–3930; https://doi.org/10.2741/2980
Published: 1 May 2008
(This article belongs to the Special Issue Computaional studies of protein aggregation)
Abstract

Amyloid-β (Aβ) peptides can elongate in the fibril axis and associate in the lateral direction. We present detailed atomic Aβ models with different in-register intermolecular β-sheet-β-sheet associations. We probe structural stability, conformational dynamics, and association force of Aβ oligomers with various sizes and structures for both wild-type and mutated sequences using molecular dynamics (MD) simulations. MD simulations show that an Aβ 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 Aβ 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 β-sheet-β-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.

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