Intrinsic determinants of Aβ(12-24) pH-dependent self-assembly revealed by combined computational and experimental studies.

The propensity of amyloid-β (Aβ) peptide to self-assemble into highly ordered amyloid structures lies at the core of their accumulation in the brain during Alzheimer's disease. By using all-atom explicit solvent replica exchange molecular dynamics simulations, we elucidated at the atomic level...

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Autores principales:	Weixin Xu, Ce Zhang, Philippe Derreumaux, Astrid Gräslund, Ludmilla Morozova-Roche, Yuguang Mu
Formato:	article
Lenguaje:	EN
Publicado:	Public Library of Science (PLoS) 2011
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/4079a91e85d845d3bf851bbc3640a3c0
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spelling	oai:doaj.org-article:4079a91e85d845d3bf851bbc3640a3c02021-11-04T06:08:09ZIntrinsic determinants of Aβ(12-24) pH-dependent self-assembly revealed by combined computational and experimental studies.1932-620310.1371/journal.pone.0024329https://doaj.org/article/4079a91e85d845d3bf851bbc3640a3c02011-01-01T00:00:00Zhttps://www.ncbi.nlm.nih.gov/pmc/articles/pmid/21957446/?tool=EBIhttps://doaj.org/toc/1932-6203The propensity of amyloid-β (Aβ) peptide to self-assemble into highly ordered amyloid structures lies at the core of their accumulation in the brain during Alzheimer's disease. By using all-atom explicit solvent replica exchange molecular dynamics simulations, we elucidated at the atomic level the intrinsic determinants of the pH-dependent dimerization of the central hydrophobic segment Aβ(12-24) and related these with the propensity to form amyloid fibrils measured by experimental tools such as atomic force microscopy and fluorescence. The process of Aβ(12-24) dimerization was evaluated in terms of free energy landscape, side-chain two-dimensional contact probability maps, β-sheet registries, potential mean force as a function of inter-chain distances, secondary structure development and radial solvation distributions. We showed that dimerization is a key event in Aβ(12-24) amyloid formation; it is highly prompted in the order of pH 5.0>2.9>>8.4 and determines further amyloid growth. The dimerization is governed by a dynamic interplay of hydrophobic, electrostatic and solvation interactions permitting some variability of β-sheets at each pH. These results provide atomistic insight into the complex process of molecular recognition detrimental for amyloid growth and pave the way for better understanding of the molecular basis of amyloid diseases.Weixin XuCe ZhangPhilippe DerreumauxAstrid GräslundLudmilla Morozova-RocheYuguang MuPublic Library of Science (PLoS)articleMedicineRScienceQENPLoS ONE, Vol 6, Iss 9, p e24329 (2011)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Weixin Xu Ce Zhang Philippe Derreumaux Astrid Gräslund Ludmilla Morozova-Roche Yuguang Mu Intrinsic determinants of Aβ(12-24) pH-dependent self-assembly revealed by combined computational and experimental studies.
description	The propensity of amyloid-β (Aβ) peptide to self-assemble into highly ordered amyloid structures lies at the core of their accumulation in the brain during Alzheimer's disease. By using all-atom explicit solvent replica exchange molecular dynamics simulations, we elucidated at the atomic level the intrinsic determinants of the pH-dependent dimerization of the central hydrophobic segment Aβ(12-24) and related these with the propensity to form amyloid fibrils measured by experimental tools such as atomic force microscopy and fluorescence. The process of Aβ(12-24) dimerization was evaluated in terms of free energy landscape, side-chain two-dimensional contact probability maps, β-sheet registries, potential mean force as a function of inter-chain distances, secondary structure development and radial solvation distributions. We showed that dimerization is a key event in Aβ(12-24) amyloid formation; it is highly prompted in the order of pH 5.0>2.9>>8.4 and determines further amyloid growth. The dimerization is governed by a dynamic interplay of hydrophobic, electrostatic and solvation interactions permitting some variability of β-sheets at each pH. These results provide atomistic insight into the complex process of molecular recognition detrimental for amyloid growth and pave the way for better understanding of the molecular basis of amyloid diseases.
format	article
author	Weixin Xu Ce Zhang Philippe Derreumaux Astrid Gräslund Ludmilla Morozova-Roche Yuguang Mu
author_facet	Weixin Xu Ce Zhang Philippe Derreumaux Astrid Gräslund Ludmilla Morozova-Roche Yuguang Mu
author_sort	Weixin Xu
title	Intrinsic determinants of Aβ(12-24) pH-dependent self-assembly revealed by combined computational and experimental studies.
title_short	Intrinsic determinants of Aβ(12-24) pH-dependent self-assembly revealed by combined computational and experimental studies.
title_full	Intrinsic determinants of Aβ(12-24) pH-dependent self-assembly revealed by combined computational and experimental studies.
title_fullStr	Intrinsic determinants of Aβ(12-24) pH-dependent self-assembly revealed by combined computational and experimental studies.
title_full_unstemmed	Intrinsic determinants of Aβ(12-24) pH-dependent self-assembly revealed by combined computational and experimental studies.
title_sort	intrinsic determinants of aβ(12-24) ph-dependent self-assembly revealed by combined computational and experimental studies.
publisher	Public Library of Science (PLoS)
publishDate	2011
url	https://doaj.org/article/4079a91e85d845d3bf851bbc3640a3c0
work_keys_str_mv	AT weixinxu intrinsicdeterminantsofab1224phdependentselfassemblyrevealedbycombinedcomputationalandexperimentalstudies AT cezhang intrinsicdeterminantsofab1224phdependentselfassemblyrevealedbycombinedcomputationalandexperimentalstudies AT philippederreumaux intrinsicdeterminantsofab1224phdependentselfassemblyrevealedbycombinedcomputationalandexperimentalstudies AT astridgraslund intrinsicdeterminantsofab1224phdependentselfassemblyrevealedbycombinedcomputationalandexperimentalstudies AT ludmillamorozovaroche intrinsicdeterminantsofab1224phdependentselfassemblyrevealedbycombinedcomputationalandexperimentalstudies AT yuguangmu intrinsicdeterminantsofab1224phdependentselfassemblyrevealedbycombinedcomputationalandexperimentalstudies
_version_	1718445145125289984

Intrinsic determinants of Aβ(12-24) pH-dependent self-assembly revealed by combined computational and experimental studies.

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