| Téléchargement | - Voir la version finale : Initial structural models of the Aβ42 dimer from replica exchange molecular dynamics simulations (PDF, 1.8 Mio)
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| DOI | Trouver le DOI : https://doi.org/10.1021/acsomega.7b00805 |
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| Auteur | Rechercher : Blinov, Nikolay1; Rechercher : Khorvash, Massih; Rechercher : Wishart, David S.1; Rechercher : Cashman, Neil R.; Rechercher : Kovalenko, Andriy1 |
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| Affiliation | - Conseil national de recherches du Canada. Nanotechnologie
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| Format | Texte, Article |
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| Sujet | glycoproteins; molecular dynamics simulation; oligomers; protein structure |
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| Résumé | Experimental characterization of the molecular structure of small amyloid (A)β oligomers that are currently considered as toxic agents in Alzheimer’s disease is a formidably difficult task due to their transient nature and tendency to aggregate. Such structural information is of importance because it can help in developing diagnostics and an effective therapy for the disease. In this study, molecular simulations and protein–protein docking are employed to explore a possible connection between the structure of Aβ monomers and the properties of the intermonomer interface in the Aβ42 dimer. A structurally diverse ensemble of conformations of the monomer was sampled in microsecond timescale implicit solvent replica exchange molecular dynamics simulations. Representative structures with different solvent exposure of hydrophobic residues and secondary structure content were selected to build structural models of the dimer. Analysis of these models reveals that formation of an intramonomer salt bridge (SB) between Asp23 and Lys28 residues can prevent the building of a hydrophobic interface between the central hydrophobic clusters (CHCs) of monomers upon dimerization. This structural feature of the Aβ42 dimer is related to the difference in packing of hydrophobic residues in monomers with the Asp23–Lys28 SB in on and off states, in particular, to a lower propensity to form hydrophobic contacts between the CHC domain and C-terminal residues in monomers with a formed SB. These findings could have important implications for understanding the difference between aggregation pathways of Aβ monomers leading to neurotoxic oligomers or inert fibrillar structures. |
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| Date de publication | 2017-11-07 |
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| Maison d’édition | American Chemical Society |
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| Dans | |
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| Langue | anglais |
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| Publications évaluées par des pairs | Oui |
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| Numéro NPARC | 23003114 |
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| Exporter la notice | Exporter en format RIS |
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| Signaler une correction | Signaler une correction (s'ouvre dans un nouvel onglet) |
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| Identificateur de l’enregistrement | f6d6252e-1bbf-45c4-b84a-764106b323d4 |
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| Enregistrement créé | 2018-04-20 |
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| Enregistrement modifié | 2020-05-30 |
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