Effects of ligands on unfolding of the amyloid β-peptide central helix: mechanistic insights from molecular dynamics simulations.

Polymerization of the amyloid β-peptide (Aβ), a process which requires that the helical structure of Aβ unfolds beforehand, is suspected to cause neurodegeneration in Alzheimer's disease. According to recent experimental studies, stabilization of the Aβ central helix counteracts Aβ polymerizati...

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Autores principales:	Mika Ito, Jan Johansson, Roger Strömberg, Lennart Nilsson
Formato:	article
Lenguaje:	EN
Publicado:	Public Library of Science (PLoS) 2012
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/728dbab85ee44765bae37d437a958946
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spelling	oai:doaj.org-article:728dbab85ee44765bae37d437a9589462021-11-18T07:29:36ZEffects of ligands on unfolding of the amyloid β-peptide central helix: mechanistic insights from molecular dynamics simulations.1932-620310.1371/journal.pone.0030510https://doaj.org/article/728dbab85ee44765bae37d437a9589462012-01-01T00:00:00Zhttps://www.ncbi.nlm.nih.gov/pmc/articles/pmid/22291970/pdf/?tool=EBIhttps://doaj.org/toc/1932-6203Polymerization of the amyloid β-peptide (Aβ), a process which requires that the helical structure of Aβ unfolds beforehand, is suspected to cause neurodegeneration in Alzheimer's disease. According to recent experimental studies, stabilization of the Aβ central helix counteracts Aβ polymerization into toxic assemblies. The effects of two ligands (Dec-DETA and Pep1b), which were designed to bind to and stabilize the Aβ central helix, on unfolding of the Aβ central helix were investigated by molecular dynamics simulations. It was quantitatively demonstrated that the stability of the Aβ central helix is increased by both ligands, and more effectively by Pep1b than by Dec-DETA. In addition, it was shown that Dec-DETA forms parallel conformations with β-strand-like Aβ, whereas Pep1b does not and instead tends to bend unwound Aβ. The molecular dynamics results correlate well with previous experiments for these ligands, which suggest that the simulation method should be useful in predicting the effectiveness of novel ligands in stabilizing the Aβ central helix. Detailed Aβ structural changes upon loss of helicity in the presence of the ligands are also revealed, which gives further insight into which ligand may lead to which path subsequent to unwinding of the Aβ central helix.Mika ItoJan JohanssonRoger StrömbergLennart NilssonPublic Library of Science (PLoS)articleMedicineRScienceQENPLoS ONE, Vol 7, Iss 1, p e30510 (2012)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Mika Ito Jan Johansson Roger Strömberg Lennart Nilsson Effects of ligands on unfolding of the amyloid β-peptide central helix: mechanistic insights from molecular dynamics simulations.
description	Polymerization of the amyloid β-peptide (Aβ), a process which requires that the helical structure of Aβ unfolds beforehand, is suspected to cause neurodegeneration in Alzheimer's disease. According to recent experimental studies, stabilization of the Aβ central helix counteracts Aβ polymerization into toxic assemblies. The effects of two ligands (Dec-DETA and Pep1b), which were designed to bind to and stabilize the Aβ central helix, on unfolding of the Aβ central helix were investigated by molecular dynamics simulations. It was quantitatively demonstrated that the stability of the Aβ central helix is increased by both ligands, and more effectively by Pep1b than by Dec-DETA. In addition, it was shown that Dec-DETA forms parallel conformations with β-strand-like Aβ, whereas Pep1b does not and instead tends to bend unwound Aβ. The molecular dynamics results correlate well with previous experiments for these ligands, which suggest that the simulation method should be useful in predicting the effectiveness of novel ligands in stabilizing the Aβ central helix. Detailed Aβ structural changes upon loss of helicity in the presence of the ligands are also revealed, which gives further insight into which ligand may lead to which path subsequent to unwinding of the Aβ central helix.
format	article
author	Mika Ito Jan Johansson Roger Strömberg Lennart Nilsson
author_facet	Mika Ito Jan Johansson Roger Strömberg Lennart Nilsson
author_sort	Mika Ito
title	Effects of ligands on unfolding of the amyloid β-peptide central helix: mechanistic insights from molecular dynamics simulations.
title_short	Effects of ligands on unfolding of the amyloid β-peptide central helix: mechanistic insights from molecular dynamics simulations.
title_full	Effects of ligands on unfolding of the amyloid β-peptide central helix: mechanistic insights from molecular dynamics simulations.
title_fullStr	Effects of ligands on unfolding of the amyloid β-peptide central helix: mechanistic insights from molecular dynamics simulations.
title_full_unstemmed	Effects of ligands on unfolding of the amyloid β-peptide central helix: mechanistic insights from molecular dynamics simulations.
title_sort	effects of ligands on unfolding of the amyloid β-peptide central helix: mechanistic insights from molecular dynamics simulations.
publisher	Public Library of Science (PLoS)
publishDate	2012
url	https://doaj.org/article/728dbab85ee44765bae37d437a958946
work_keys_str_mv	AT mikaito effectsofligandsonunfoldingoftheamyloidbpeptidecentralhelixmechanisticinsightsfrommoleculardynamicssimulations AT janjohansson effectsofligandsonunfoldingoftheamyloidbpeptidecentralhelixmechanisticinsightsfrommoleculardynamicssimulations AT rogerstromberg effectsofligandsonunfoldingoftheamyloidbpeptidecentralhelixmechanisticinsightsfrommoleculardynamicssimulations AT lennartnilsson effectsofligandsonunfoldingoftheamyloidbpeptidecentralhelixmechanisticinsightsfrommoleculardynamicssimulations
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Effects of ligands on unfolding of the amyloid β-peptide central helix: mechanistic insights from molecular dynamics simulations.

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