Examining the Ensembles of Amyloid-β Monomer Variants and Their Propensities to Form Fibers Using an Energy Landscape Visualization Method
Autor(a) principal: | |
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Data de Publicação: | 2022 |
Outros Autores: | , , , , |
Tipo de documento: | Artigo |
Idioma: | eng |
Título da fonte: | Repositório Institucional da UNESP |
Texto Completo: | http://dx.doi.org/10.1021/acs.jpcb.1c08525 http://hdl.handle.net/11449/230218 |
Resumo: | The amyloid-β (Aβ) monomer, an intrinsically disordered peptide, is produced by the cleavage of the amyloid precursor protein, leading to Aβ-40 and Aβ-42 as major products. These two isoforms generate pathological aggregates, whose accumulation correlates with Alzheimer’s disease (AD). Experiments have shown that even though the natural abundance of Aβ-42 is smaller than that for Aβ-40, the Aβ-42 is more aggregation-prone compared to Aβ-40. Moreover, several single-point mutations are associated with early onset forms of AD. This work analyzes coarse-grained associative-memory, water-mediated, structure and energy model (AWSEM) simulations of normal Aβ-40 and Aβ-42 monomers, along with six single-point mutations associated with early onset disease. We analyzed the simulations using the energy landscape visualization method (ELViM), a reaction-coordinate-free approach suited to explore the frustrated energy landscapes of intrinsically disordered proteins. ELViM is shown to distinguish the monomer ensembles of variants that rapidly form fibers from those that do not form fibers as readily. It also delineates the amino acid contacts characterizing each ensemble. The results shed light on the potential of ELViM to probe intrinsically disordered proteins. |
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Examining the Ensembles of Amyloid-β Monomer Variants and Their Propensities to Form Fibers Using an Energy Landscape Visualization MethodThe amyloid-β (Aβ) monomer, an intrinsically disordered peptide, is produced by the cleavage of the amyloid precursor protein, leading to Aβ-40 and Aβ-42 as major products. These two isoforms generate pathological aggregates, whose accumulation correlates with Alzheimer’s disease (AD). Experiments have shown that even though the natural abundance of Aβ-42 is smaller than that for Aβ-40, the Aβ-42 is more aggregation-prone compared to Aβ-40. Moreover, several single-point mutations are associated with early onset forms of AD. This work analyzes coarse-grained associative-memory, water-mediated, structure and energy model (AWSEM) simulations of normal Aβ-40 and Aβ-42 monomers, along with six single-point mutations associated with early onset disease. We analyzed the simulations using the energy landscape visualization method (ELViM), a reaction-coordinate-free approach suited to explore the frustrated energy landscapes of intrinsically disordered proteins. ELViM is shown to distinguish the monomer ensembles of variants that rapidly form fibers from those that do not form fibers as readily. It also delineates the amino acid contacts characterizing each ensemble. The results shed light on the potential of ELViM to probe intrinsically disordered proteins.Department of Physics Institute of Biosciences Humanities and Exact Sciences São Paulo State University (UNESP), São José do Rio PretoCenter for Theoretical Biological Physics Rice UniversityDepartments of Physics and Astronomy Chemistry and Biosciences Rice UniversityDepartment of Physics Institute of Biosciences Humanities and Exact Sciences São Paulo State University (UNESP), São José do Rio PretoUniversidade Estadual Paulista (UNESP)Rice UniversitySanches, Murilo N. [UNESP]Knapp, KaitlinOliveira, Antonio B.Wolynes, Peter G.Onuchic, José N.Leite, Vitor B. P. [UNESP]2022-04-29T08:38:36Z2022-04-29T08:38:36Z2022-01-13info:eu-repo/semantics/publishedVersioninfo:eu-repo/semantics/article93-99http://dx.doi.org/10.1021/acs.jpcb.1c08525Journal of Physical Chemistry B, v. 126, n. 1, p. 93-99, 2022.1520-52071520-6106http://hdl.handle.net/11449/23021810.1021/acs.jpcb.1c085252-s2.0-85122838167Scopusreponame:Repositório Institucional da UNESPinstname:Universidade Estadual Paulista (UNESP)instacron:UNESPengJournal of Physical Chemistry Binfo:eu-repo/semantics/openAccess2022-04-29T08:38:36Zoai:repositorio.unesp.br:11449/230218Repositório InstitucionalPUBhttp://repositorio.unesp.br/oai/requestopendoar:29462024-08-06T00:05:45.388944Repositório Institucional da UNESP - Universidade Estadual Paulista (UNESP)false |
dc.title.none.fl_str_mv |
Examining the Ensembles of Amyloid-β Monomer Variants and Their Propensities to Form Fibers Using an Energy Landscape Visualization Method |
title |
Examining the Ensembles of Amyloid-β Monomer Variants and Their Propensities to Form Fibers Using an Energy Landscape Visualization Method |
spellingShingle |
Examining the Ensembles of Amyloid-β Monomer Variants and Their Propensities to Form Fibers Using an Energy Landscape Visualization Method Sanches, Murilo N. [UNESP] |
title_short |
Examining the Ensembles of Amyloid-β Monomer Variants and Their Propensities to Form Fibers Using an Energy Landscape Visualization Method |
title_full |
Examining the Ensembles of Amyloid-β Monomer Variants and Their Propensities to Form Fibers Using an Energy Landscape Visualization Method |
title_fullStr |
Examining the Ensembles of Amyloid-β Monomer Variants and Their Propensities to Form Fibers Using an Energy Landscape Visualization Method |
title_full_unstemmed |
Examining the Ensembles of Amyloid-β Monomer Variants and Their Propensities to Form Fibers Using an Energy Landscape Visualization Method |
title_sort |
Examining the Ensembles of Amyloid-β Monomer Variants and Their Propensities to Form Fibers Using an Energy Landscape Visualization Method |
author |
Sanches, Murilo N. [UNESP] |
author_facet |
Sanches, Murilo N. [UNESP] Knapp, Kaitlin Oliveira, Antonio B. Wolynes, Peter G. Onuchic, José N. Leite, Vitor B. P. [UNESP] |
author_role |
author |
author2 |
Knapp, Kaitlin Oliveira, Antonio B. Wolynes, Peter G. Onuchic, José N. Leite, Vitor B. P. [UNESP] |
author2_role |
author author author author author |
dc.contributor.none.fl_str_mv |
Universidade Estadual Paulista (UNESP) Rice University |
dc.contributor.author.fl_str_mv |
Sanches, Murilo N. [UNESP] Knapp, Kaitlin Oliveira, Antonio B. Wolynes, Peter G. Onuchic, José N. Leite, Vitor B. P. [UNESP] |
description |
The amyloid-β (Aβ) monomer, an intrinsically disordered peptide, is produced by the cleavage of the amyloid precursor protein, leading to Aβ-40 and Aβ-42 as major products. These two isoforms generate pathological aggregates, whose accumulation correlates with Alzheimer’s disease (AD). Experiments have shown that even though the natural abundance of Aβ-42 is smaller than that for Aβ-40, the Aβ-42 is more aggregation-prone compared to Aβ-40. Moreover, several single-point mutations are associated with early onset forms of AD. This work analyzes coarse-grained associative-memory, water-mediated, structure and energy model (AWSEM) simulations of normal Aβ-40 and Aβ-42 monomers, along with six single-point mutations associated with early onset disease. We analyzed the simulations using the energy landscape visualization method (ELViM), a reaction-coordinate-free approach suited to explore the frustrated energy landscapes of intrinsically disordered proteins. ELViM is shown to distinguish the monomer ensembles of variants that rapidly form fibers from those that do not form fibers as readily. It also delineates the amino acid contacts characterizing each ensemble. The results shed light on the potential of ELViM to probe intrinsically disordered proteins. |
publishDate |
2022 |
dc.date.none.fl_str_mv |
2022-04-29T08:38:36Z 2022-04-29T08:38:36Z 2022-01-13 |
dc.type.status.fl_str_mv |
info:eu-repo/semantics/publishedVersion |
dc.type.driver.fl_str_mv |
info:eu-repo/semantics/article |
format |
article |
status_str |
publishedVersion |
dc.identifier.uri.fl_str_mv |
http://dx.doi.org/10.1021/acs.jpcb.1c08525 Journal of Physical Chemistry B, v. 126, n. 1, p. 93-99, 2022. 1520-5207 1520-6106 http://hdl.handle.net/11449/230218 10.1021/acs.jpcb.1c08525 2-s2.0-85122838167 |
url |
http://dx.doi.org/10.1021/acs.jpcb.1c08525 http://hdl.handle.net/11449/230218 |
identifier_str_mv |
Journal of Physical Chemistry B, v. 126, n. 1, p. 93-99, 2022. 1520-5207 1520-6106 10.1021/acs.jpcb.1c08525 2-s2.0-85122838167 |
dc.language.iso.fl_str_mv |
eng |
language |
eng |
dc.relation.none.fl_str_mv |
Journal of Physical Chemistry B |
dc.rights.driver.fl_str_mv |
info:eu-repo/semantics/openAccess |
eu_rights_str_mv |
openAccess |
dc.format.none.fl_str_mv |
93-99 |
dc.source.none.fl_str_mv |
Scopus reponame:Repositório Institucional da UNESP instname:Universidade Estadual Paulista (UNESP) instacron:UNESP |
instname_str |
Universidade Estadual Paulista (UNESP) |
instacron_str |
UNESP |
institution |
UNESP |
reponame_str |
Repositório Institucional da UNESP |
collection |
Repositório Institucional da UNESP |
repository.name.fl_str_mv |
Repositório Institucional da UNESP - Universidade Estadual Paulista (UNESP) |
repository.mail.fl_str_mv |
|
_version_ |
1808129581858684928 |