Unfolding of the amyloid β-peptide central helix: mechanistic insights from molecular dynamics simulations.

Alzheimer's disease (AD) pathogenesis is associated with formation of amyloid fibrils caused by polymerization of the amyloid β-peptide (Aβ), which is a process that requires unfolding of the native helical structure of Aβ. According to recent experimental studies, stabilization of the Aβ centr...

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Autores principales:	Mika Ito, Jan Johansson, Roger Strömberg, Lennart Nilsson
Formato:	article
Lenguaje:	EN
Publicado:	Public Library of Science (PLoS) 2011
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/a62e90095c0f409d8333a5146d877a1b
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spelling	oai:doaj.org-article:a62e90095c0f409d8333a5146d877a1b2021-11-18T06:57:41ZUnfolding of the amyloid β-peptide central helix: mechanistic insights from molecular dynamics simulations.1932-620310.1371/journal.pone.0017587https://doaj.org/article/a62e90095c0f409d8333a5146d877a1b2011-03-01T00:00:00Zhttps://www.ncbi.nlm.nih.gov/pmc/articles/pmid/21408230/?tool=EBIhttps://doaj.org/toc/1932-6203Alzheimer's disease (AD) pathogenesis is associated with formation of amyloid fibrils caused by polymerization of the amyloid β-peptide (Aβ), which is a process that requires unfolding of the native helical structure of Aβ. According to recent experimental studies, stabilization of the Aβ central helix is effective in preventing Aβ polymerization into toxic assemblies. To uncover the fundamental mechanism of unfolding of the Aβ central helix, we performed molecular dynamics simulations for wild-type (WT), V18A/F19A/F20A mutant (MA), and V18L/F19L/F20L mutant (ML) models of the Aβ central helix. It was quantitatively demonstrated that the stability of the α-helical conformation of both MA and ML is higher than that of WT, indicating that the α-helical propensity of the three nonpolar residues (18, 19, and 20) is the main factor for the stability of the whole Aβ central helix and that their hydrophobicity plays a secondary role. WT was found to completely unfold by a three-step mechanism: 1) loss of α-helical backbone hydrogen bonds, 2) strong interactions between nonpolar sidechains, and 3) strong interactions between polar sidechains. WT did not completely unfold in cases when any of the three steps was omitted. MA and ML did not completely unfold mainly due to the lack of the first step. This suggests that disturbances in any of the three steps would be effective in inhibiting the unfolding of the Aβ central helix. Our findings would pave the way for design of new drugs to prevent or retard AD.Mika ItoJan JohanssonRoger StrömbergLennart NilssonPublic Library of Science (PLoS)articleMedicineRScienceQENPLoS ONE, Vol 6, Iss 3, p e17587 (2011)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Mika Ito Jan Johansson Roger Strömberg Lennart Nilsson Unfolding of the amyloid β-peptide central helix: mechanistic insights from molecular dynamics simulations.
description	Alzheimer's disease (AD) pathogenesis is associated with formation of amyloid fibrils caused by polymerization of the amyloid β-peptide (Aβ), which is a process that requires unfolding of the native helical structure of Aβ. According to recent experimental studies, stabilization of the Aβ central helix is effective in preventing Aβ polymerization into toxic assemblies. To uncover the fundamental mechanism of unfolding of the Aβ central helix, we performed molecular dynamics simulations for wild-type (WT), V18A/F19A/F20A mutant (MA), and V18L/F19L/F20L mutant (ML) models of the Aβ central helix. It was quantitatively demonstrated that the stability of the α-helical conformation of both MA and ML is higher than that of WT, indicating that the α-helical propensity of the three nonpolar residues (18, 19, and 20) is the main factor for the stability of the whole Aβ central helix and that their hydrophobicity plays a secondary role. WT was found to completely unfold by a three-step mechanism: 1) loss of α-helical backbone hydrogen bonds, 2) strong interactions between nonpolar sidechains, and 3) strong interactions between polar sidechains. WT did not completely unfold in cases when any of the three steps was omitted. MA and ML did not completely unfold mainly due to the lack of the first step. This suggests that disturbances in any of the three steps would be effective in inhibiting the unfolding of the Aβ central helix. Our findings would pave the way for design of new drugs to prevent or retard AD.
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	Unfolding of the amyloid β-peptide central helix: mechanistic insights from molecular dynamics simulations.
title_short	Unfolding of the amyloid β-peptide central helix: mechanistic insights from molecular dynamics simulations.
title_full	Unfolding of the amyloid β-peptide central helix: mechanistic insights from molecular dynamics simulations.
title_fullStr	Unfolding of the amyloid β-peptide central helix: mechanistic insights from molecular dynamics simulations.
title_full_unstemmed	Unfolding of the amyloid β-peptide central helix: mechanistic insights from molecular dynamics simulations.
title_sort	unfolding of the amyloid β-peptide central helix: mechanistic insights from molecular dynamics simulations.
publisher	Public Library of Science (PLoS)
publishDate	2011
url	https://doaj.org/article/a62e90095c0f409d8333a5146d877a1b
work_keys_str_mv	AT mikaito unfoldingoftheamyloidbpeptidecentralhelixmechanisticinsightsfrommoleculardynamicssimulations AT janjohansson unfoldingoftheamyloidbpeptidecentralhelixmechanisticinsightsfrommoleculardynamicssimulations AT rogerstromberg unfoldingoftheamyloidbpeptidecentralhelixmechanisticinsightsfrommoleculardynamicssimulations AT lennartnilsson unfoldingoftheamyloidbpeptidecentralhelixmechanisticinsightsfrommoleculardynamicssimulations
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Unfolding of the amyloid β-peptide central helix: mechanistic insights from molecular dynamics simulations.

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