Free cholesterol induces higher β-sheet content in Aβ peptide oligomers by aromatic interaction with Phe19.

Accumulating experimental evidence support an enhancing effect of free cholesterol on amyloid-beta (Aβ) aggregation. To probe the mechanisms of cholesterol-mediated Aβ aggregation, we applied all-atom molecular dynamic simulations on Aβ42 peptides in presence of free cholesterol. Several control sys...

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Autores principales:	Xiaolin Zhou, Jie Xu
Formato:	article
Lenguaje:	EN
Publicado:	Public Library of Science (PLoS) 2012
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/bd04a645056041c888c328462e153e28
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spelling	oai:doaj.org-article:bd04a645056041c888c328462e153e282021-11-18T08:14:01ZFree cholesterol induces higher β-sheet content in Aβ peptide oligomers by aromatic interaction with Phe19.1932-620310.1371/journal.pone.0046245https://doaj.org/article/bd04a645056041c888c328462e153e282012-01-01T00:00:00Zhttps://www.ncbi.nlm.nih.gov/pmc/articles/pmid/23049991/pdf/?tool=EBIhttps://doaj.org/toc/1932-6203Accumulating experimental evidence support an enhancing effect of free cholesterol on amyloid-beta (Aβ) aggregation. To probe the mechanisms of cholesterol-mediated Aβ aggregation, we applied all-atom molecular dynamic simulations on Aβ42 peptides in presence of free cholesterol. Several control systems were also designed to examine the specificity of cholesterol-residue interactions, including mutation on aromatic residue, substitution of cholesterol with sphingomyelin (SM) and DPPC bilayer, and a mixing SM and cholesterol. Each system was performed 4 independent simulations, with a total time of 560 ns. It was found that cholesterol increased β-sheet formation by 4 folds, but the Phe19→Ser mutation on Aβ42 peptide totally eliminated cholesterol's effect. A stable contact was recognized between the steroid group of cholesterol and the Benzyl group of Phe19. Interestingly, our simulation revealed a regular 1 ns time interval between the establishment of cholesterol-phenylalanine contact and consequent β-sheet formation, suggesting an important role of steroid-benzyl interaction in cholesterol-mediated aggregation. The presence of SM slightly increased β-sheet formation, but the mixture of cholesterol and SM had a strong induction effect. Also, the measurement of Phe19-lipid distance indicates that aromatic side chains of peptides prone to bind to cholesterol on the surface of the mixed micelle. In the DPPC system, polar chains were attracted to the surface of membrane, yielding moderate increase of β-sheet formation. These results shed light on the mechanism of cholesterol-mediated fibrillogenesis, and help to differentiate the effects of cholesterol and other lipids on β-sheet formation process.Xiaolin ZhouJie XuPublic Library of Science (PLoS)articleMedicineRScienceQENPLoS ONE, Vol 7, Iss 9, p e46245 (2012)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Xiaolin Zhou Jie Xu Free cholesterol induces higher β-sheet content in Aβ peptide oligomers by aromatic interaction with Phe19.
description	Accumulating experimental evidence support an enhancing effect of free cholesterol on amyloid-beta (Aβ) aggregation. To probe the mechanisms of cholesterol-mediated Aβ aggregation, we applied all-atom molecular dynamic simulations on Aβ42 peptides in presence of free cholesterol. Several control systems were also designed to examine the specificity of cholesterol-residue interactions, including mutation on aromatic residue, substitution of cholesterol with sphingomyelin (SM) and DPPC bilayer, and a mixing SM and cholesterol. Each system was performed 4 independent simulations, with a total time of 560 ns. It was found that cholesterol increased β-sheet formation by 4 folds, but the Phe19→Ser mutation on Aβ42 peptide totally eliminated cholesterol's effect. A stable contact was recognized between the steroid group of cholesterol and the Benzyl group of Phe19. Interestingly, our simulation revealed a regular 1 ns time interval between the establishment of cholesterol-phenylalanine contact and consequent β-sheet formation, suggesting an important role of steroid-benzyl interaction in cholesterol-mediated aggregation. The presence of SM slightly increased β-sheet formation, but the mixture of cholesterol and SM had a strong induction effect. Also, the measurement of Phe19-lipid distance indicates that aromatic side chains of peptides prone to bind to cholesterol on the surface of the mixed micelle. In the DPPC system, polar chains were attracted to the surface of membrane, yielding moderate increase of β-sheet formation. These results shed light on the mechanism of cholesterol-mediated fibrillogenesis, and help to differentiate the effects of cholesterol and other lipids on β-sheet formation process.
format	article
author	Xiaolin Zhou Jie Xu
author_facet	Xiaolin Zhou Jie Xu
author_sort	Xiaolin Zhou
title	Free cholesterol induces higher β-sheet content in Aβ peptide oligomers by aromatic interaction with Phe19.
title_short	Free cholesterol induces higher β-sheet content in Aβ peptide oligomers by aromatic interaction with Phe19.
title_full	Free cholesterol induces higher β-sheet content in Aβ peptide oligomers by aromatic interaction with Phe19.
title_fullStr	Free cholesterol induces higher β-sheet content in Aβ peptide oligomers by aromatic interaction with Phe19.
title_full_unstemmed	Free cholesterol induces higher β-sheet content in Aβ peptide oligomers by aromatic interaction with Phe19.
title_sort	free cholesterol induces higher β-sheet content in aβ peptide oligomers by aromatic interaction with phe19.
publisher	Public Library of Science (PLoS)
publishDate	2012
url	https://doaj.org/article/bd04a645056041c888c328462e153e28
work_keys_str_mv	AT xiaolinzhou freecholesterolinduceshigherbsheetcontentinabpeptideoligomersbyaromaticinteractionwithphe19 AT jiexu freecholesterolinduceshigherbsheetcontentinabpeptideoligomersbyaromaticinteractionwithphe19
_version_	1718422066788564992

Free cholesterol induces higher β-sheet content in Aβ peptide oligomers by aromatic interaction with Phe19.

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