Zinc Induced Aβ16 Aggregation Modeled by Molecular Dynamics

It is widely accepted that the addition of zinc leads to the formation of neurotoxic nonfibrillar aggregates of beta-amyloid peptides Aβ40 and Aβ42 and at the same time destabilizes amyloid fibrils. However, the mechanism of the effect of zinc on beta-am...

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Autores principales:	Anna P. Tolstova, Alexander A. Makarov, Alexei A. Adzhubei
Formato:	article
Lenguaje:	EN
Publicado:	MDPI AG 2021
Materias:	Aβ<sub>16</sub> aggregation metal binding site zinc ion MD beta-amyloid Biology (General) QH301-705.5 Chemistry QD1-999
Acceso en línea:	https://doaj.org/article/34cefd6210014001a4fa12e5b3beecab
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spelling	oai:doaj.org-article:34cefd6210014001a4fa12e5b3beecab2021-11-25T17:54:01ZZinc Induced Aβ<sub>16</sub> Aggregation Modeled by Molecular Dynamics10.3390/ijms2222121611422-00671661-6596https://doaj.org/article/34cefd6210014001a4fa12e5b3beecab2021-11-01T00:00:00Zhttps://www.mdpi.com/1422-0067/22/22/12161https://doaj.org/toc/1661-6596https://doaj.org/toc/1422-0067It is widely accepted that the addition of zinc leads to the formation of neurotoxic nonfibrillar aggregates of beta-amyloid peptides Aβ<sub>40</sub> and Aβ<sub>42</sub> and at the same time destabilizes amyloid fibrils. However, the mechanism of the effect of zinc on beta-amyloid is not fully understood. In this study, a fast zinc-induced aggregation of Aβ<sub>16</sub> (as compared to a system without zinc) via the formation of Aβ<sub>16</sub> dimers with one zinc ion coordinated in the metal-binding site <sub>11</sub>EVHH<sub>14</sub>, followed by their polymerization, has been studied by molecular dynamics. The best aggregation was shown by the system composed of Aβ<sub>16</sub> dimers bound by one zinc ion, with no additional zinc in solution. The presence of Aβ<sub>16</sub> dimers was a major condition, sufficient for fast aggregation into larger complexes. It has been shown that the addition of zinc to a system with already formed dimers does not substantially affect the characteristics and rate of aggregation. At the same time, an excessive concentration of zinc at the early stages of the formation of conglomerates can negatively affect aggregation, since in systems where zinc ions occupied the <sub>11</sub>EVHH<sub>14</sub> coordination center and the His6 residue of every Aβ<sub>16</sub> monomer, the aggregation proceeded more slowly and the resulting complexes were not as large as in the zinc-free Aβ system. Thus, this study has shown that the formation of Aβ<sub>16</sub> dimers bound through zinc ions at the <sub>11</sub>EVHH<sub>14</sub> sites of the peptides plays an important role in the formation of neurotoxic non-fibrillar aggregates of beta-amyloid peptide Aβ<sub>16</sub>. The best energetically favorable structure has been obtained for the complex of two Aβ<sub>16</sub> dimers with two zinc ions.Anna P. TolstovaAlexander A. MakarovAlexei A. AdzhubeiMDPI AGarticleAβ<sub>16</sub>aggregationmetal binding sitezinc ionMDbeta-amyloidBiology (General)QH301-705.5ChemistryQD1-999ENInternational Journal of Molecular Sciences, Vol 22, Iss 12161, p 12161 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	Aβ<sub>16</sub> aggregation metal binding site zinc ion MD beta-amyloid Biology (General) QH301-705.5 Chemistry QD1-999
spellingShingle	Aβ<sub>16</sub> aggregation metal binding site zinc ion MD beta-amyloid Biology (General) QH301-705.5 Chemistry QD1-999 Anna P. Tolstova Alexander A. Makarov Alexei A. Adzhubei Zinc Induced Aβ<sub>16</sub> Aggregation Modeled by Molecular Dynamics
description	It is widely accepted that the addition of zinc leads to the formation of neurotoxic nonfibrillar aggregates of beta-amyloid peptides Aβ<sub>40</sub> and Aβ<sub>42</sub> and at the same time destabilizes amyloid fibrils. However, the mechanism of the effect of zinc on beta-amyloid is not fully understood. In this study, a fast zinc-induced aggregation of Aβ<sub>16</sub> (as compared to a system without zinc) via the formation of Aβ<sub>16</sub> dimers with one zinc ion coordinated in the metal-binding site <sub>11</sub>EVHH<sub>14</sub>, followed by their polymerization, has been studied by molecular dynamics. The best aggregation was shown by the system composed of Aβ<sub>16</sub> dimers bound by one zinc ion, with no additional zinc in solution. The presence of Aβ<sub>16</sub> dimers was a major condition, sufficient for fast aggregation into larger complexes. It has been shown that the addition of zinc to a system with already formed dimers does not substantially affect the characteristics and rate of aggregation. At the same time, an excessive concentration of zinc at the early stages of the formation of conglomerates can negatively affect aggregation, since in systems where zinc ions occupied the <sub>11</sub>EVHH<sub>14</sub> coordination center and the His6 residue of every Aβ<sub>16</sub> monomer, the aggregation proceeded more slowly and the resulting complexes were not as large as in the zinc-free Aβ system. Thus, this study has shown that the formation of Aβ<sub>16</sub> dimers bound through zinc ions at the <sub>11</sub>EVHH<sub>14</sub> sites of the peptides plays an important role in the formation of neurotoxic non-fibrillar aggregates of beta-amyloid peptide Aβ<sub>16</sub>. The best energetically favorable structure has been obtained for the complex of two Aβ<sub>16</sub> dimers with two zinc ions.
format	article
author	Anna P. Tolstova Alexander A. Makarov Alexei A. Adzhubei
author_facet	Anna P. Tolstova Alexander A. Makarov Alexei A. Adzhubei
author_sort	Anna P. Tolstova
title	Zinc Induced Aβ<sub>16</sub> Aggregation Modeled by Molecular Dynamics
title_short	Zinc Induced Aβ<sub>16</sub> Aggregation Modeled by Molecular Dynamics
title_full	Zinc Induced Aβ<sub>16</sub> Aggregation Modeled by Molecular Dynamics
title_fullStr	Zinc Induced Aβ<sub>16</sub> Aggregation Modeled by Molecular Dynamics
title_full_unstemmed	Zinc Induced Aβ<sub>16</sub> Aggregation Modeled by Molecular Dynamics
title_sort	zinc induced aβ<sub>16</sub> aggregation modeled by molecular dynamics
publisher	MDPI AG
publishDate	2021
url	https://doaj.org/article/34cefd6210014001a4fa12e5b3beecab
work_keys_str_mv	AT annaptolstova zincinducedabsub16subaggregationmodeledbymoleculardynamics AT alexanderamakarov zincinducedabsub16subaggregationmodeledbymoleculardynamics AT alexeiaadzhubei zincinducedabsub16subaggregationmodeledbymoleculardynamics
_version_	1718411856641523712

Zinc Induced Aβ<sub>16</sub> Aggregation Modeled by Molecular Dynamics

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