Weaker N-Terminal Interactions for the Protective over the Causative Aβ Peptide Dimer Mutants

ACS Chemical Neuroscience
Bhanushee SharmaGeorges Belfort

Abstract

Knowing that abeta amyloid peptide (Aβ42) dimers are the smallest and most abundant neurotoxic oligomers for Alzheimer's disease (AD), we used molecular simulations with advanced sampling methods (replica-exchange) to characterize and compare interactions between the N-termini (residues 1-16) of wild type (WT-WT) and five mutant dimers under constrained and unconstrained conditions. The number of contacts and distances between the N-termini, and contact maps of their conformational landscape illustrate substantial differences for a single residue change. The N-terminal contacts are significantly diminished for the dimers containing the monomers that protect against (WT-A2T) as compared with those that predispose toward (A2V-A2V) AD and for the control WT-WT dimers. The reduced number of N-terminal contacts not only occurs at or near the second residue mutations but also is distributed through to the 10th residue. These findings provide added support to the accumulating evidence for the "N-terminal hypothesis of AD" and offer an alternate mechanism for the cause of protection from the A2T mutant.

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Citations

May 7, 2020·Scientific Reports·Shayon BhattacharyaDamien Thompson
Oct 8, 2020·Journal of Neurochemistry·Colleen S LimegroverSusan M Catalano
Mar 7, 2021·International Journal of Molecular Sciences·Satoru G Itoh, Hisashi Okumura
Jul 13, 2021·The Journal of Physical Chemistry. B·Clifford MorrisDeguo Du
Apr 12, 2019·Chemical Reviews·Ioana M Ilie, Amedeo Caflisch
Nov 13, 2020·The Journal of Physical Chemistry. B·Hoang Linh NguyenMai Suan Li

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