Computational study on the allosteric mechanism of Leishmania major IF4E-1 by 4E-interacting protein-1: Unravelling the determinants of m7GTP cap recognition
Autor(a) principal: | |
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Data de Publicação: | 2021 |
Outros Autores: | , , , , , |
Tipo de documento: | Artigo |
Idioma: | eng |
Título da fonte: | Repositório Institucional da UNESP |
Texto Completo: | http://dx.doi.org/10.1016/j.csbj.2021.03.036 http://hdl.handle.net/11449/228930 |
Resumo: | During their life cycle, Leishmania parasites display a fine-tuned regulation of the mRNA translation through the differential expression of isoforms of eukaryotic translation initiation factor 4E (LeishIF4Es). The interaction between allosteric modulators such as 4E-interacting proteins (4E-IPs) and LeishIF4E affects the affinity of this initiation factor for the mRNA cap. Here, several computational approaches were employed to elucidate the molecular bases of the previously-reported allosteric modulation in L. major exerted by 4E-IP1 (Lm4E-IP1) on eukaryotic translation initiation factor 4E 1 (LmIF4E-1). Molecular dynamics (MD) simulations and accurate binding free energy calculations (ΔGbind) were combined with network-based modeling of residue-residue correlations. We also describe the differences in internal motions of LmIF4E-1 apo form, cap-bound, and Lm4E-IP1-bound systems. Through community network calculations, the differences in the allosteric pathways of allosterically-inhibited and active forms of LmIF4E-1 were revealed. The ΔGbind values show significant differences between the active and inhibited systems, which are in agreement with the available experimental data. Our study thoroughly describes the dynamical perturbations of LmIF4E-1 cap-binding site triggered by Lm4E-IP1. These findings are not only essential for the understanding of a critical process of trypanosomatids’ gene expression but also for gaining insight into the allostery of eukaryotic IF4Es, which could be useful for structure-based design of drugs against this protein family. |
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Repositório Institucional da UNESP |
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Computational study on the allosteric mechanism of Leishmania major IF4E-1 by 4E-interacting protein-1: Unravelling the determinants of m7GTP cap recognition4E-binding proteinsAdaptive Biasing Force (ABF) calculationsAllosteryEukaryotic Initiation Factor-4ELeishmania majorMolecular dynamicsmRNA capDuring their life cycle, Leishmania parasites display a fine-tuned regulation of the mRNA translation through the differential expression of isoforms of eukaryotic translation initiation factor 4E (LeishIF4Es). The interaction between allosteric modulators such as 4E-interacting proteins (4E-IPs) and LeishIF4E affects the affinity of this initiation factor for the mRNA cap. Here, several computational approaches were employed to elucidate the molecular bases of the previously-reported allosteric modulation in L. major exerted by 4E-IP1 (Lm4E-IP1) on eukaryotic translation initiation factor 4E 1 (LmIF4E-1). Molecular dynamics (MD) simulations and accurate binding free energy calculations (ΔGbind) were combined with network-based modeling of residue-residue correlations. We also describe the differences in internal motions of LmIF4E-1 apo form, cap-bound, and Lm4E-IP1-bound systems. Through community network calculations, the differences in the allosteric pathways of allosterically-inhibited and active forms of LmIF4E-1 were revealed. The ΔGbind values show significant differences between the active and inhibited systems, which are in agreement with the available experimental data. Our study thoroughly describes the dynamical perturbations of LmIF4E-1 cap-binding site triggered by Lm4E-IP1. These findings are not only essential for the understanding of a critical process of trypanosomatids’ gene expression but also for gaining insight into the allostery of eukaryotic IF4Es, which could be useful for structure-based design of drugs against this protein family.Fundação de Amparo à Pesquisa do Estado do Rio de Janeiro (FAPERJ)Department of Physics Instituto de Biociências Letras e Ciências Exatas Universidade Estadual Paulista Julio de Mesquita Filho São José do Rio PretoCenter for Theoretical Biological Physics Rice UniversityInstituto de Biofísica Carlos Chagas Filho Universidade Federal do Rio de JaneiroDepartment of Physics Instituto de Biociências Letras e Ciências Exatas Universidade Estadual Paulista Julio de Mesquita Filho São José do Rio PretoUniversidade Estadual Paulista (UNESP)Rice UniversityUniversidade Federal do Rio de Janeiro (UFRJ)Hernández-Alvarez, Lilian [UNESP]Oliveira Jr, Antonio B [UNESP]Hernández-González, Jorge Enrique [UNESP]Chahine, Jorge [UNESP]Pascutti, Pedro Geraldode Araujo, Alexandre Suman [UNESP]de Souza, Fátima Pereira [UNESP]2022-04-29T08:29:28Z2022-04-29T08:29:28Z2021-01-01info:eu-repo/semantics/publishedVersioninfo:eu-repo/semantics/article2027-2044http://dx.doi.org/10.1016/j.csbj.2021.03.036Computational and Structural Biotechnology Journal, v. 19, p. 2027-2044.2001-0370http://hdl.handle.net/11449/22893010.1016/j.csbj.2021.03.0362-s2.0-85104351533Scopusreponame:Repositório Institucional da UNESPinstname:Universidade Estadual Paulista (UNESP)instacron:UNESPengComputational and Structural Biotechnology Journalinfo:eu-repo/semantics/openAccess2022-04-29T08:29:28Zoai:repositorio.unesp.br:11449/228930Repositório InstitucionalPUBhttp://repositorio.unesp.br/oai/requestopendoar:29462024-08-05T17:30:50.600988Repositório Institucional da UNESP - Universidade Estadual Paulista (UNESP)false |
dc.title.none.fl_str_mv |
Computational study on the allosteric mechanism of Leishmania major IF4E-1 by 4E-interacting protein-1: Unravelling the determinants of m7GTP cap recognition |
title |
Computational study on the allosteric mechanism of Leishmania major IF4E-1 by 4E-interacting protein-1: Unravelling the determinants of m7GTP cap recognition |
spellingShingle |
Computational study on the allosteric mechanism of Leishmania major IF4E-1 by 4E-interacting protein-1: Unravelling the determinants of m7GTP cap recognition Hernández-Alvarez, Lilian [UNESP] 4E-binding proteins Adaptive Biasing Force (ABF) calculations Allostery Eukaryotic Initiation Factor-4E Leishmania major Molecular dynamics mRNA cap |
title_short |
Computational study on the allosteric mechanism of Leishmania major IF4E-1 by 4E-interacting protein-1: Unravelling the determinants of m7GTP cap recognition |
title_full |
Computational study on the allosteric mechanism of Leishmania major IF4E-1 by 4E-interacting protein-1: Unravelling the determinants of m7GTP cap recognition |
title_fullStr |
Computational study on the allosteric mechanism of Leishmania major IF4E-1 by 4E-interacting protein-1: Unravelling the determinants of m7GTP cap recognition |
title_full_unstemmed |
Computational study on the allosteric mechanism of Leishmania major IF4E-1 by 4E-interacting protein-1: Unravelling the determinants of m7GTP cap recognition |
title_sort |
Computational study on the allosteric mechanism of Leishmania major IF4E-1 by 4E-interacting protein-1: Unravelling the determinants of m7GTP cap recognition |
author |
Hernández-Alvarez, Lilian [UNESP] |
author_facet |
Hernández-Alvarez, Lilian [UNESP] Oliveira Jr, Antonio B [UNESP] Hernández-González, Jorge Enrique [UNESP] Chahine, Jorge [UNESP] Pascutti, Pedro Geraldo de Araujo, Alexandre Suman [UNESP] de Souza, Fátima Pereira [UNESP] |
author_role |
author |
author2 |
Oliveira Jr, Antonio B [UNESP] Hernández-González, Jorge Enrique [UNESP] Chahine, Jorge [UNESP] Pascutti, Pedro Geraldo de Araujo, Alexandre Suman [UNESP] de Souza, Fátima Pereira [UNESP] |
author2_role |
author author author author author author |
dc.contributor.none.fl_str_mv |
Universidade Estadual Paulista (UNESP) Rice University Universidade Federal do Rio de Janeiro (UFRJ) |
dc.contributor.author.fl_str_mv |
Hernández-Alvarez, Lilian [UNESP] Oliveira Jr, Antonio B [UNESP] Hernández-González, Jorge Enrique [UNESP] Chahine, Jorge [UNESP] Pascutti, Pedro Geraldo de Araujo, Alexandre Suman [UNESP] de Souza, Fátima Pereira [UNESP] |
dc.subject.por.fl_str_mv |
4E-binding proteins Adaptive Biasing Force (ABF) calculations Allostery Eukaryotic Initiation Factor-4E Leishmania major Molecular dynamics mRNA cap |
topic |
4E-binding proteins Adaptive Biasing Force (ABF) calculations Allostery Eukaryotic Initiation Factor-4E Leishmania major Molecular dynamics mRNA cap |
description |
During their life cycle, Leishmania parasites display a fine-tuned regulation of the mRNA translation through the differential expression of isoforms of eukaryotic translation initiation factor 4E (LeishIF4Es). The interaction between allosteric modulators such as 4E-interacting proteins (4E-IPs) and LeishIF4E affects the affinity of this initiation factor for the mRNA cap. Here, several computational approaches were employed to elucidate the molecular bases of the previously-reported allosteric modulation in L. major exerted by 4E-IP1 (Lm4E-IP1) on eukaryotic translation initiation factor 4E 1 (LmIF4E-1). Molecular dynamics (MD) simulations and accurate binding free energy calculations (ΔGbind) were combined with network-based modeling of residue-residue correlations. We also describe the differences in internal motions of LmIF4E-1 apo form, cap-bound, and Lm4E-IP1-bound systems. Through community network calculations, the differences in the allosteric pathways of allosterically-inhibited and active forms of LmIF4E-1 were revealed. The ΔGbind values show significant differences between the active and inhibited systems, which are in agreement with the available experimental data. Our study thoroughly describes the dynamical perturbations of LmIF4E-1 cap-binding site triggered by Lm4E-IP1. These findings are not only essential for the understanding of a critical process of trypanosomatids’ gene expression but also for gaining insight into the allostery of eukaryotic IF4Es, which could be useful for structure-based design of drugs against this protein family. |
publishDate |
2021 |
dc.date.none.fl_str_mv |
2021-01-01 2022-04-29T08:29:28Z 2022-04-29T08:29:28Z |
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/10.1016/j.csbj.2021.03.036 Computational and Structural Biotechnology Journal, v. 19, p. 2027-2044. 2001-0370 http://hdl.handle.net/11449/228930 10.1016/j.csbj.2021.03.036 2-s2.0-85104351533 |
url |
http://dx.doi.org/10.1016/j.csbj.2021.03.036 http://hdl.handle.net/11449/228930 |
identifier_str_mv |
Computational and Structural Biotechnology Journal, v. 19, p. 2027-2044. 2001-0370 10.1016/j.csbj.2021.03.036 2-s2.0-85104351533 |
dc.language.iso.fl_str_mv |
eng |
language |
eng |
dc.relation.none.fl_str_mv |
Computational and Structural Biotechnology Journal |
dc.rights.driver.fl_str_mv |
info:eu-repo/semantics/openAccess |
eu_rights_str_mv |
openAccess |
dc.format.none.fl_str_mv |
2027-2044 |
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_ |
1808128820523302912 |