Exploring the Folding Mechanism of Dimeric Superoxide Dismutase
Autor(a) principal: | |
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Data de Publicação: | 2023 |
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.2c08877 http://hdl.handle.net/11449/249621 |
Resumo: | The Cu/Zn Human Superoxide Dismutase (SOD1) is a dimeric metalloenzyme whose genetic mutations are directly related to amyotrophic lateral sclerosis (ALS), so understanding its folding mechanism is of fundamental importance. Currently, the SOD1 dimer formation is studied via molecular dynamics simulations using a simplified structure-based model and an all-atom model. Results from the simplified model reveal a mechanism dependent on distances between monomers, which are limited by constraints to mimic concentration dependence. The stability of intermediates (during the int state) is significantly affected by this distance, as well as by the presence of two folded monomers prior to dimer formation. The kinetics of interface formation are also highly dependent on the separation distance. The folding temperature of the dimer is about 4.2% higher than that of the monomer, a value not too different from experimental data. All-atom simulations on the apo dimer give binding free energy between monomers similar to experimental values. An intermediate state is evident for the apo form at a separation distance between monomers slightly larger than the native distance which has little formed interface between monomers. We have shown that this intermediate is stabilized by non-native intra- and intercontacts. |
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Repositório Institucional da UNESP |
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Exploring the Folding Mechanism of Dimeric Superoxide DismutaseThe Cu/Zn Human Superoxide Dismutase (SOD1) is a dimeric metalloenzyme whose genetic mutations are directly related to amyotrophic lateral sclerosis (ALS), so understanding its folding mechanism is of fundamental importance. Currently, the SOD1 dimer formation is studied via molecular dynamics simulations using a simplified structure-based model and an all-atom model. Results from the simplified model reveal a mechanism dependent on distances between monomers, which are limited by constraints to mimic concentration dependence. The stability of intermediates (during the int state) is significantly affected by this distance, as well as by the presence of two folded monomers prior to dimer formation. The kinetics of interface formation are also highly dependent on the separation distance. The folding temperature of the dimer is about 4.2% higher than that of the monomer, a value not too different from experimental data. All-atom simulations on the apo dimer give binding free energy between monomers similar to experimental values. An intermediate state is evident for the apo form at a separation distance between monomers slightly larger than the native distance which has little formed interface between monomers. We have shown that this intermediate is stabilized by non-native intra- and intercontacts.Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES)Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)São Paulo State University (UNESP)São Paulo State University (UNESP)Universidade Estadual Paulista (UNESP)Mouro, Paulo R. [UNESP]Sanches, Murilo N. [UNESP]Leite, Vitor B. P. [UNESP]Chahine, Jorge [UNESP]2023-07-29T16:04:43Z2023-07-29T16:04:43Z2023-02-16info:eu-repo/semantics/publishedVersioninfo:eu-repo/semantics/article1338-1349http://dx.doi.org/10.1021/acs.jpcb.2c08877Journal of Physical Chemistry B, v. 127, n. 6, p. 1338-1349, 2023.1520-52071520-6106http://hdl.handle.net/11449/24962110.1021/acs.jpcb.2c088772-s2.0-85147209701Scopusreponame:Repositório Institucional da UNESPinstname:Universidade Estadual Paulista (UNESP)instacron:UNESPengJournal of Physical Chemistry Binfo:eu-repo/semantics/openAccess2023-07-29T16:04:43Zoai:repositorio.unesp.br:11449/249621Repositório InstitucionalPUBhttp://repositorio.unesp.br/oai/requestopendoar:29462024-08-05T23:48:30.624233Repositório Institucional da UNESP - Universidade Estadual Paulista (UNESP)false |
dc.title.none.fl_str_mv |
Exploring the Folding Mechanism of Dimeric Superoxide Dismutase |
title |
Exploring the Folding Mechanism of Dimeric Superoxide Dismutase |
spellingShingle |
Exploring the Folding Mechanism of Dimeric Superoxide Dismutase Mouro, Paulo R. [UNESP] |
title_short |
Exploring the Folding Mechanism of Dimeric Superoxide Dismutase |
title_full |
Exploring the Folding Mechanism of Dimeric Superoxide Dismutase |
title_fullStr |
Exploring the Folding Mechanism of Dimeric Superoxide Dismutase |
title_full_unstemmed |
Exploring the Folding Mechanism of Dimeric Superoxide Dismutase |
title_sort |
Exploring the Folding Mechanism of Dimeric Superoxide Dismutase |
author |
Mouro, Paulo R. [UNESP] |
author_facet |
Mouro, Paulo R. [UNESP] Sanches, Murilo N. [UNESP] Leite, Vitor B. P. [UNESP] Chahine, Jorge [UNESP] |
author_role |
author |
author2 |
Sanches, Murilo N. [UNESP] Leite, Vitor B. P. [UNESP] Chahine, Jorge [UNESP] |
author2_role |
author author author |
dc.contributor.none.fl_str_mv |
Universidade Estadual Paulista (UNESP) |
dc.contributor.author.fl_str_mv |
Mouro, Paulo R. [UNESP] Sanches, Murilo N. [UNESP] Leite, Vitor B. P. [UNESP] Chahine, Jorge [UNESP] |
description |
The Cu/Zn Human Superoxide Dismutase (SOD1) is a dimeric metalloenzyme whose genetic mutations are directly related to amyotrophic lateral sclerosis (ALS), so understanding its folding mechanism is of fundamental importance. Currently, the SOD1 dimer formation is studied via molecular dynamics simulations using a simplified structure-based model and an all-atom model. Results from the simplified model reveal a mechanism dependent on distances between monomers, which are limited by constraints to mimic concentration dependence. The stability of intermediates (during the int state) is significantly affected by this distance, as well as by the presence of two folded monomers prior to dimer formation. The kinetics of interface formation are also highly dependent on the separation distance. The folding temperature of the dimer is about 4.2% higher than that of the monomer, a value not too different from experimental data. All-atom simulations on the apo dimer give binding free energy between monomers similar to experimental values. An intermediate state is evident for the apo form at a separation distance between monomers slightly larger than the native distance which has little formed interface between monomers. We have shown that this intermediate is stabilized by non-native intra- and intercontacts. |
publishDate |
2023 |
dc.date.none.fl_str_mv |
2023-07-29T16:04:43Z 2023-07-29T16:04:43Z 2023-02-16 |
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.2c08877 Journal of Physical Chemistry B, v. 127, n. 6, p. 1338-1349, 2023. 1520-5207 1520-6106 http://hdl.handle.net/11449/249621 10.1021/acs.jpcb.2c08877 2-s2.0-85147209701 |
url |
http://dx.doi.org/10.1021/acs.jpcb.2c08877 http://hdl.handle.net/11449/249621 |
identifier_str_mv |
Journal of Physical Chemistry B, v. 127, n. 6, p. 1338-1349, 2023. 1520-5207 1520-6106 10.1021/acs.jpcb.2c08877 2-s2.0-85147209701 |
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 |
1338-1349 |
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_ |
1808129553983340544 |