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Int. J. Mol. Sci. 2018, 19(2), 571; https://doi.org/10.3390/ijms19020571

Conformational Dynamics and Stability of U-Shaped and S-Shaped Amyloid β Assemblies

1
Istituto Dalle Molle di Studi sull’Intelligenza Artificiale (IDSIA), Scuola Universitaria Professionale della Svizzera Italiana (SUPSI), Università della Svizzera Italiana (USI), Centro Galleria 2, CH-6928 Manno, Switzerland
2
Department of Mechanical and Aerospace Engineering, Politecnico di Torino, Corso Duca degli Abruzzi 24, IT-10128 Torino, Italy
3
Department of Physics, University of Alberta, Edmonton, AB T6G 2R3, Canada
*
Authors to whom correspondence should be addressed.
Received: 10 January 2018 / Revised: 4 February 2018 / Accepted: 10 February 2018 / Published: 14 February 2018
(This article belongs to the Special Issue Protein Structural Dynamics)
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Abstract

Alzheimer’s disease is the most fatal neurodegenerative disorder characterized by the aggregation and deposition of Amyloid β (Aβ) oligomers in the brain of patients. Two principal variants of Aβ exist in humans: Aβ1–40 and Aβ1–42. The former is the most abundant in the plaques, while the latter is the most toxic species and forms fibrils more rapidly. Interestingly, fibrils of Aβ1–40 peptides can only assume U-shaped conformations while Aβ1–42 can also arrange as S-shaped three-stranded chains, as recently discovered. As alterations in protein conformational arrangement correlate with cell toxicity and speed of disease progression, it is important to characterize, at molecular level, the conformational dynamics of amyloid fibrils. In this work, Replica Exchange Molecular Dynamics simulations were carried out to compare the conformational dynamics of U-shaped and S-shaped Aβ17–42 small fibrils. Our computational results provide support for the stability of the recently proposed S-shaped model due to the maximized interactions involving the C-terminal residues. On the other hand, the U-shaped motif is characterized by significant distortions resulting in a more disordered assembly. Outcomes of our work suggest that the molecular architecture of the protein aggregates might play a pivotal role in formation and conformational stability of the resulting fibrils. View Full-Text
Keywords: Alzheimer’s disease; amyloid β; replica exchange; molecular dynamics; U-shaped; S-shaped; assembly; fibril; gromacs; aggregation Alzheimer’s disease; amyloid β; replica exchange; molecular dynamics; U-shaped; S-shaped; assembly; fibril; gromacs; aggregation
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This is an open access article distributed under the Creative Commons Attribution License which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. (CC BY 4.0).

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Grasso, G.; Rebella, M.; Muscat, S.; Morbiducci, U.; Tuszynski, J.; Danani, A.; Deriu, M.A. Conformational Dynamics and Stability of U-Shaped and S-Shaped Amyloid β Assemblies. Int. J. Mol. Sci. 2018, 19, 571.

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