Alzheimer’s disease (AD) is a neurodegenerative disease characterized by extracellular aggregation of amyloid-β (Aβ) in toxic, soluble oligomers and insoluble plaques. The underlying cause of AD is unknown, but studies have shown that several familial AD (FAD) mutations lead to early onset and a more severe form of the disease. The “Iowa” D23N, “Arctic” E22G, “Italian” E22K, and “Dutch” E22Q variants of Aβ contain charge-altering mutations that have been shown to accelerate the rate of aggregation relative to the wild-type (WT) peptide. To gain a greater understanding of how amyloidogenic proteins unfold and why these specific mutations lead to more severe clinical manifestations, we used unbiased molecular dynamics (MD) and umbrella sampling (US) simulations. US allows us to investigate the differences in the folding free energy of WT and the FAD mutants of model Aβ<sub>15-27</sub> α-helical fragments with the CHARMM36m (C36m) nonpolarizable and Drude polarizable force fields (FF). We found that C36m produces unfavorable folding free energies, whereas folding is favorable in the Drude FF, with subtle differences between the WT peptide and each of the FAD mutants that were not observed with C36m. In addition, we performed unbiased MD simulations on WT and mutated Aβ<sub>1-42</sub> starting from helical and unfolded conformations to further understand if tertiary interactions modulate stability. We found that conformational changes were faster using C36m than with the Drude FF, but the kinetics of the polarizable model are likely more realistic. Use of the Drude polarizable FF allows us to analyze how electrostatic interactions, including those between permanent and induced dipoles, affect side-chain properties, salt bridges, and hydration on folding free energies and the conformational ensembles of the full-length peptides. Our results help describe how familial mutations alter the free energy of folding and disrupt secondary and tertiary structure implicated in early onset and rapid aggregation.

Effect of familial Alzheimer's disease mutations of the folding free energy of amyloid β-peptide

Macromolecular Chemistry: The Second Century

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ACS Spring 2020 National Meeting & Expo

The official archive and repository for all ACS Meetings & Expositions abstracts and select posters or presentations.