Molecular dynamics study of Zn(aβ) and Zn(aβ)2.

The aggregation of Aβ-peptide (Aβ) is widely considered to be the critical step in the pathology of Alzheimer's disease. Small, soluble Aβ oligomers have been shown to be more neurotoxic than large, insoluble aggregates and fibrils. Recent studies suggest that biometal ions, including Zn(II), m...

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Autores principales:	Lurong Pan, James C Patterson
Formato:	article
Lenguaje:	EN
Publicado:	Public Library of Science (PLoS) 2013
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/f28a6834129c4883845db378d5779fdb
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spelling	oai:doaj.org-article:f28a6834129c4883845db378d5779fdb2021-11-18T08:53:23ZMolecular dynamics study of Zn(aβ) and Zn(aβ)2.1932-620310.1371/journal.pone.0070681https://doaj.org/article/f28a6834129c4883845db378d5779fdb2013-01-01T00:00:00Zhttps://www.ncbi.nlm.nih.gov/pmc/articles/pmid/24086248/pdf/?tool=EBIhttps://doaj.org/toc/1932-6203The aggregation of Aβ-peptide (Aβ) is widely considered to be the critical step in the pathology of Alzheimer's disease. Small, soluble Aβ oligomers have been shown to be more neurotoxic than large, insoluble aggregates and fibrils. Recent studies suggest that biometal ions, including Zn(II), may play an important role in the aggregation process. Experimentally determining the details of the binding process is complicated by the kinetic lability of zinc. To study the dynamic nature of the zinc-bound Aβ complexes and the potential mechanisms by which Zn(II) affects Aβ oligomerization we have performed atomistic molecular dynamics (MD) simulations of Zn(Aβ) and Zn(Aβ)2. The models were based on NMR data and predicted coordination environments from previous density functional theory calculations. When modeled as 4-coordinate covalently bound Zn(Aβ) n complexes (where n = 1 or 2), zinc imposes conformational changes in the surrounding Aβ residues. Moreover, zinc reduces the helix content and increases the random coil content of the full peptide. Although zinc binds at the N-terminus of Aβ, β-sheet formation is observed exclusively at the C-terminus in the Zn(Aβ) and most of the Zn(Aβ)2 complexes. Furthermore, initial binding to zinc promotes the formation of intra-chain salt-bridges, while subsequent dissociation promotes the formation of inter-chain salt-bridges. These results suggest that Zn-binding to Aβ accelerates the aggregation of Aβ by unfolding the helical structure in Aβ peptide and stabilizing the formation of vital salt-bridges within and between Aβ peptides.Lurong PanJames C PattersonPublic Library of Science (PLoS)articleMedicineRScienceQENPLoS ONE, Vol 8, Iss 9, p e70681 (2013)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Lurong Pan James C Patterson Molecular dynamics study of Zn(aβ) and Zn(aβ)2.
description	The aggregation of Aβ-peptide (Aβ) is widely considered to be the critical step in the pathology of Alzheimer's disease. Small, soluble Aβ oligomers have been shown to be more neurotoxic than large, insoluble aggregates and fibrils. Recent studies suggest that biometal ions, including Zn(II), may play an important role in the aggregation process. Experimentally determining the details of the binding process is complicated by the kinetic lability of zinc. To study the dynamic nature of the zinc-bound Aβ complexes and the potential mechanisms by which Zn(II) affects Aβ oligomerization we have performed atomistic molecular dynamics (MD) simulations of Zn(Aβ) and Zn(Aβ)2. The models were based on NMR data and predicted coordination environments from previous density functional theory calculations. When modeled as 4-coordinate covalently bound Zn(Aβ) n complexes (where n = 1 or 2), zinc imposes conformational changes in the surrounding Aβ residues. Moreover, zinc reduces the helix content and increases the random coil content of the full peptide. Although zinc binds at the N-terminus of Aβ, β-sheet formation is observed exclusively at the C-terminus in the Zn(Aβ) and most of the Zn(Aβ)2 complexes. Furthermore, initial binding to zinc promotes the formation of intra-chain salt-bridges, while subsequent dissociation promotes the formation of inter-chain salt-bridges. These results suggest that Zn-binding to Aβ accelerates the aggregation of Aβ by unfolding the helical structure in Aβ peptide and stabilizing the formation of vital salt-bridges within and between Aβ peptides.
format	article
author	Lurong Pan James C Patterson
author_facet	Lurong Pan James C Patterson
author_sort	Lurong Pan
title	Molecular dynamics study of Zn(aβ) and Zn(aβ)2.
title_short	Molecular dynamics study of Zn(aβ) and Zn(aβ)2.
title_full	Molecular dynamics study of Zn(aβ) and Zn(aβ)2.
title_fullStr	Molecular dynamics study of Zn(aβ) and Zn(aβ)2.
title_full_unstemmed	Molecular dynamics study of Zn(aβ) and Zn(aβ)2.
title_sort	molecular dynamics study of zn(aβ) and zn(aβ)2.
publisher	Public Library of Science (PLoS)
publishDate	2013
url	https://doaj.org/article/f28a6834129c4883845db378d5779fdb
work_keys_str_mv	AT lurongpan moleculardynamicsstudyofznabandznab2 AT jamescpatterson moleculardynamicsstudyofznabandznab2
_version_	1718421238486925312

Molecular dynamics study of Zn(aβ) and Zn(aβ)2.

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