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In Silico Analysis of the Apolipoprotein E and the Amyloid β Peptide Interaction: Misfolding Induced by Frustration of the Salt Bridge Network

The relationship between Apolipoprotein E (ApoE) and the aggregation processes of the amyloid β (Aβ) peptide has been shown to be crucial for Alzheimer's disease (AD). The presence of the ApoE4 isoform is considered to be a contributing risk factor for AD. However, the detailed molecular proper...

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Autores principales: Luo, Jinghui, Maréchal, Jean-Didier, Wärmländer, Sebastian, Gräslund, Astrid, Perálvarez-Marín, Alex
Formato: Texto
Lenguaje:English
Publicado: Public Library of Science 2010
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2816681/
https://www.ncbi.nlm.nih.gov/pubmed/20140182
http://dx.doi.org/10.1371/journal.pcbi.1000663
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author Luo, Jinghui
Maréchal, Jean-Didier
Wärmländer, Sebastian
Gräslund, Astrid
Perálvarez-Marín, Alex
author_facet Luo, Jinghui
Maréchal, Jean-Didier
Wärmländer, Sebastian
Gräslund, Astrid
Perálvarez-Marín, Alex
author_sort Luo, Jinghui
collection PubMed
description The relationship between Apolipoprotein E (ApoE) and the aggregation processes of the amyloid β (Aβ) peptide has been shown to be crucial for Alzheimer's disease (AD). The presence of the ApoE4 isoform is considered to be a contributing risk factor for AD. However, the detailed molecular properties of ApoE4 interacting with the Aβ peptide are unknown, although various mechanisms have been proposed to explain the physiological and pathological role of this relationship. Here, computer simulations have been used to investigate the process of Aβ interaction with the N-terminal domain of the human ApoE isoforms (ApoE2, ApoE3 and ApoE4). Molecular docking combined with molecular dynamics simulations have been undertaken to determine the Aβ peptide binding sites and the relative stability of binding to each of the ApoE isoforms. Our results show that from the several ApoE isoforms investigated, only ApoE4 presents a misfolded intermediate when bound to Aβ. Moreover, the initial α-helix used as the Aβ peptide model structure also becomes unstructured due to the interaction with ApoE4. These structural changes appear to be related to a rearrangement of the salt bridge network in ApoE4, for which we propose a model. It seems plausible that ApoE4 in its partially unfolded state is incapable of performing the clearance of Aβ, thereby promoting amyloid forming processes. Hence, the proposed model can be used to identify potential drug binding sites in the ApoE4-Aβ complex, where the interaction between the two molecules can be inhibited.
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spelling pubmed-28166812010-02-07 In Silico Analysis of the Apolipoprotein E and the Amyloid β Peptide Interaction: Misfolding Induced by Frustration of the Salt Bridge Network Luo, Jinghui Maréchal, Jean-Didier Wärmländer, Sebastian Gräslund, Astrid Perálvarez-Marín, Alex PLoS Comput Biol Research Article The relationship between Apolipoprotein E (ApoE) and the aggregation processes of the amyloid β (Aβ) peptide has been shown to be crucial for Alzheimer's disease (AD). The presence of the ApoE4 isoform is considered to be a contributing risk factor for AD. However, the detailed molecular properties of ApoE4 interacting with the Aβ peptide are unknown, although various mechanisms have been proposed to explain the physiological and pathological role of this relationship. Here, computer simulations have been used to investigate the process of Aβ interaction with the N-terminal domain of the human ApoE isoforms (ApoE2, ApoE3 and ApoE4). Molecular docking combined with molecular dynamics simulations have been undertaken to determine the Aβ peptide binding sites and the relative stability of binding to each of the ApoE isoforms. Our results show that from the several ApoE isoforms investigated, only ApoE4 presents a misfolded intermediate when bound to Aβ. Moreover, the initial α-helix used as the Aβ peptide model structure also becomes unstructured due to the interaction with ApoE4. These structural changes appear to be related to a rearrangement of the salt bridge network in ApoE4, for which we propose a model. It seems plausible that ApoE4 in its partially unfolded state is incapable of performing the clearance of Aβ, thereby promoting amyloid forming processes. Hence, the proposed model can be used to identify potential drug binding sites in the ApoE4-Aβ complex, where the interaction between the two molecules can be inhibited. Public Library of Science 2010-02-05 /pmc/articles/PMC2816681/ /pubmed/20140182 http://dx.doi.org/10.1371/journal.pcbi.1000663 Text en Luo et al. http://creativecommons.org/licenses/by/4.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are properly credited.
spellingShingle Research Article
Luo, Jinghui
Maréchal, Jean-Didier
Wärmländer, Sebastian
Gräslund, Astrid
Perálvarez-Marín, Alex
In Silico Analysis of the Apolipoprotein E and the Amyloid β Peptide Interaction: Misfolding Induced by Frustration of the Salt Bridge Network
title In Silico Analysis of the Apolipoprotein E and the Amyloid β Peptide Interaction: Misfolding Induced by Frustration of the Salt Bridge Network
title_full In Silico Analysis of the Apolipoprotein E and the Amyloid β Peptide Interaction: Misfolding Induced by Frustration of the Salt Bridge Network
title_fullStr In Silico Analysis of the Apolipoprotein E and the Amyloid β Peptide Interaction: Misfolding Induced by Frustration of the Salt Bridge Network
title_full_unstemmed In Silico Analysis of the Apolipoprotein E and the Amyloid β Peptide Interaction: Misfolding Induced by Frustration of the Salt Bridge Network
title_short In Silico Analysis of the Apolipoprotein E and the Amyloid β Peptide Interaction: Misfolding Induced by Frustration of the Salt Bridge Network
title_sort in silico analysis of the apolipoprotein e and the amyloid β peptide interaction: misfolding induced by frustration of the salt bridge network
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2816681/
https://www.ncbi.nlm.nih.gov/pubmed/20140182
http://dx.doi.org/10.1371/journal.pcbi.1000663
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