Structural and thermodynamic characteristics of the exosite binding pocket on the human BACE1: A molecular modeling approach
- Autores
- Gutierrez, Lucas Joel; Enriz, Ricardo Daniel; Baldoni, Hector Armando
- Año de publicación
- 2010
- Idioma
- inglés
- Tipo de recurso
- artículo
- Estado
- versión publicada
- Descripción
- We report a molecular modeling study aimed to locate and provide the full structural characteristics of the exosite binding site of the BACE1. A three-step procedure was followed. In the first stage, we performed blind docking studies on the whole target surface. In a second stage, the mode of binding was further refined by molecular dynamics (MD) simulation. Finally, binding free energy calculations, through the MM-PBSA protocol, were carried out to gain insight into the stability and thermodynamics of the inhibitor located at the selected binding pockets. Twelve binding pockets were identified on the surface of BACE1 by blind docking studies. The calculations of binding free energies for the 12 complexes show that van der Waals interactions dominate the mode of binding of these complexes. The best ranked complex shows that residues Glu255-Pro258, Phe261, Gly264-Ala272, Asp311-Ala313, Ser315, and Asp317-Tyr320 are located within ∼6 Å from the INH located at the exosite. The hydrogen bonds formed between the INH peptide, residues Tyr1, Tyr3, and Leu7 with the BACE1 residues Leu267, Cys269, Trp270, Asp311, and Asp 317 can strengthen the binding of the BACE1-INH complex.
Fil: Gutierrez, Lucas Joel. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - San Luis. Instituto Multidisciplinario de Investigaciones Biológicas de San Luis. Universidad Nacional de San Luis. Facultad de Ciencias Físico Matemáticas y Naturales. Instituto Multidisciplinario de Investigaciones Biológicas de San Luis; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Nordeste. Instituto de Química Básica y Aplicada del Nordeste Argentino. Universidad Nacional del Nordeste. Facultad de Ciencias Exactas Naturales y Agrimensura. Instituto de Química Básica y Aplicada del Nordeste Argentino; Argentina. Universidad Nacional de San Luis. Facultad de Química, Bioquímica y Farmacia. Área Química General e Inorgánica; Argentina
Fil: Enriz, Ricardo Daniel. Universidad Nacional de San Luis. Facultad de Química, Bioquímica y Farmacia. Área Química General e Inorgánica; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - San Luis. Instituto Multidisciplinario de Investigaciones Biológicas de San Luis. Universidad Nacional de San Luis. Facultad de Ciencias Físico Matemáticas y Naturales. Instituto Multidisciplinario de Investigaciones Biológicas de San Luis; Argentina
Fil: Baldoni, Hector Armando. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - San Luis. Instituto de Matemática Aplicada de San Luis "Prof. Ezio Marchi". Universidad Nacional de San Luis. Facultad de Ciencias Físico, Matemáticas y Naturales. Instituto de Matemática Aplicada de San Luis "Prof. Ezio Marchi"; Argentina. Universidad Nacional de San Luis. Facultad de Química, Bioquímica y Farmacia. Área Química General e Inorgánica; Argentina - Materia
-
BACE1
Allosteric site
Docking
Molecular dynamics simulations - Nivel de accesibilidad
- acceso abierto
- Condiciones de uso
- https://creativecommons.org/licenses/by-nc-sa/2.5/ar/
- Repositorio
- Institución
- Consejo Nacional de Investigaciones Científicas y Técnicas
- OAI Identificador
- oai:ri.conicet.gov.ar:11336/141177
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Structural and thermodynamic characteristics of the exosite binding pocket on the human BACE1: A molecular modeling approachGutierrez, Lucas JoelEnriz, Ricardo DanielBaldoni, Hector ArmandoBACE1Allosteric siteDockingMolecular dynamics simulationshttps://purl.org/becyt/ford/1.7https://purl.org/becyt/ford/1We report a molecular modeling study aimed to locate and provide the full structural characteristics of the exosite binding site of the BACE1. A three-step procedure was followed. In the first stage, we performed blind docking studies on the whole target surface. In a second stage, the mode of binding was further refined by molecular dynamics (MD) simulation. Finally, binding free energy calculations, through the MM-PBSA protocol, were carried out to gain insight into the stability and thermodynamics of the inhibitor located at the selected binding pockets. Twelve binding pockets were identified on the surface of BACE1 by blind docking studies. The calculations of binding free energies for the 12 complexes show that van der Waals interactions dominate the mode of binding of these complexes. The best ranked complex shows that residues Glu255-Pro258, Phe261, Gly264-Ala272, Asp311-Ala313, Ser315, and Asp317-Tyr320 are located within ∼6 Å from the INH located at the exosite. The hydrogen bonds formed between the INH peptide, residues Tyr1, Tyr3, and Leu7 with the BACE1 residues Leu267, Cys269, Trp270, Asp311, and Asp 317 can strengthen the binding of the BACE1-INH complex.Fil: Gutierrez, Lucas Joel. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - San Luis. Instituto Multidisciplinario de Investigaciones Biológicas de San Luis. Universidad Nacional de San Luis. Facultad de Ciencias Físico Matemáticas y Naturales. Instituto Multidisciplinario de Investigaciones Biológicas de San Luis; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Nordeste. Instituto de Química Básica y Aplicada del Nordeste Argentino. Universidad Nacional del Nordeste. Facultad de Ciencias Exactas Naturales y Agrimensura. Instituto de Química Básica y Aplicada del Nordeste Argentino; Argentina. Universidad Nacional de San Luis. Facultad de Química, Bioquímica y Farmacia. Área Química General e Inorgánica; ArgentinaFil: Enriz, Ricardo Daniel. Universidad Nacional de San Luis. Facultad de Química, Bioquímica y Farmacia. Área Química General e Inorgánica; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - San Luis. Instituto Multidisciplinario de Investigaciones Biológicas de San Luis. Universidad Nacional de San Luis. Facultad de Ciencias Físico Matemáticas y Naturales. Instituto Multidisciplinario de Investigaciones Biológicas de San Luis; ArgentinaFil: Baldoni, Hector Armando. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - San Luis. Instituto de Matemática Aplicada de San Luis "Prof. Ezio Marchi". Universidad Nacional de San Luis. Facultad de Ciencias Físico, Matemáticas y Naturales. Instituto de Matemática Aplicada de San Luis "Prof. Ezio Marchi"; Argentina. Universidad Nacional de San Luis. Facultad de Química, Bioquímica y Farmacia. Área Química General e Inorgánica; ArgentinaAmerican Chemical Society2010-09-23info:eu-repo/semantics/articleinfo:eu-repo/semantics/publishedVersionhttp://purl.org/coar/resource_type/c_6501info:ar-repo/semantics/articuloapplication/pdfapplication/pdfapplication/pdfapplication/pdfhttp://hdl.handle.net/11336/141177Gutierrez, Lucas Joel; Enriz, Ricardo Daniel; Baldoni, Hector Armando; Structural and thermodynamic characteristics of the exosite binding pocket on the human BACE1: A molecular modeling approach; American Chemical Society; Journal of Physical Chemistry A; 114; 37; 23-9-2010; 10261-102691089-56391520-5215CONICET DigitalCONICETenginfo:eu-repo/semantics/altIdentifier/url/https://pubs.acs.org/doi/10.1021/jp104983ainfo:eu-repo/semantics/altIdentifier/doi/10.1021/jp104983ainfo:eu-repo/semantics/openAccesshttps://creativecommons.org/licenses/by-nc-sa/2.5/ar/reponame:CONICET Digital (CONICET)instname:Consejo Nacional de Investigaciones Científicas y Técnicas2025-09-29T10:04:58Zoai:ri.conicet.gov.ar:11336/141177instacron:CONICETInstitucionalhttp://ri.conicet.gov.ar/Organismo científico-tecnológicoNo correspondehttp://ri.conicet.gov.ar/oai/requestdasensio@conicet.gov.ar; lcarlino@conicet.gov.arArgentinaNo correspondeNo correspondeNo correspondeopendoar:34982025-09-29 10:04:58.689CONICET Digital (CONICET) - Consejo Nacional de Investigaciones Científicas y Técnicasfalse |
dc.title.none.fl_str_mv |
Structural and thermodynamic characteristics of the exosite binding pocket on the human BACE1: A molecular modeling approach |
title |
Structural and thermodynamic characteristics of the exosite binding pocket on the human BACE1: A molecular modeling approach |
spellingShingle |
Structural and thermodynamic characteristics of the exosite binding pocket on the human BACE1: A molecular modeling approach Gutierrez, Lucas Joel BACE1 Allosteric site Docking Molecular dynamics simulations |
title_short |
Structural and thermodynamic characteristics of the exosite binding pocket on the human BACE1: A molecular modeling approach |
title_full |
Structural and thermodynamic characteristics of the exosite binding pocket on the human BACE1: A molecular modeling approach |
title_fullStr |
Structural and thermodynamic characteristics of the exosite binding pocket on the human BACE1: A molecular modeling approach |
title_full_unstemmed |
Structural and thermodynamic characteristics of the exosite binding pocket on the human BACE1: A molecular modeling approach |
title_sort |
Structural and thermodynamic characteristics of the exosite binding pocket on the human BACE1: A molecular modeling approach |
dc.creator.none.fl_str_mv |
Gutierrez, Lucas Joel Enriz, Ricardo Daniel Baldoni, Hector Armando |
author |
Gutierrez, Lucas Joel |
author_facet |
Gutierrez, Lucas Joel Enriz, Ricardo Daniel Baldoni, Hector Armando |
author_role |
author |
author2 |
Enriz, Ricardo Daniel Baldoni, Hector Armando |
author2_role |
author author |
dc.subject.none.fl_str_mv |
BACE1 Allosteric site Docking Molecular dynamics simulations |
topic |
BACE1 Allosteric site Docking Molecular dynamics simulations |
purl_subject.fl_str_mv |
https://purl.org/becyt/ford/1.7 https://purl.org/becyt/ford/1 |
dc.description.none.fl_txt_mv |
We report a molecular modeling study aimed to locate and provide the full structural characteristics of the exosite binding site of the BACE1. A three-step procedure was followed. In the first stage, we performed blind docking studies on the whole target surface. In a second stage, the mode of binding was further refined by molecular dynamics (MD) simulation. Finally, binding free energy calculations, through the MM-PBSA protocol, were carried out to gain insight into the stability and thermodynamics of the inhibitor located at the selected binding pockets. Twelve binding pockets were identified on the surface of BACE1 by blind docking studies. The calculations of binding free energies for the 12 complexes show that van der Waals interactions dominate the mode of binding of these complexes. The best ranked complex shows that residues Glu255-Pro258, Phe261, Gly264-Ala272, Asp311-Ala313, Ser315, and Asp317-Tyr320 are located within ∼6 Å from the INH located at the exosite. The hydrogen bonds formed between the INH peptide, residues Tyr1, Tyr3, and Leu7 with the BACE1 residues Leu267, Cys269, Trp270, Asp311, and Asp 317 can strengthen the binding of the BACE1-INH complex. Fil: Gutierrez, Lucas Joel. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - San Luis. Instituto Multidisciplinario de Investigaciones Biológicas de San Luis. Universidad Nacional de San Luis. Facultad de Ciencias Físico Matemáticas y Naturales. Instituto Multidisciplinario de Investigaciones Biológicas de San Luis; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Nordeste. Instituto de Química Básica y Aplicada del Nordeste Argentino. Universidad Nacional del Nordeste. Facultad de Ciencias Exactas Naturales y Agrimensura. Instituto de Química Básica y Aplicada del Nordeste Argentino; Argentina. Universidad Nacional de San Luis. Facultad de Química, Bioquímica y Farmacia. Área Química General e Inorgánica; Argentina Fil: Enriz, Ricardo Daniel. Universidad Nacional de San Luis. Facultad de Química, Bioquímica y Farmacia. Área Química General e Inorgánica; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - San Luis. Instituto Multidisciplinario de Investigaciones Biológicas de San Luis. Universidad Nacional de San Luis. Facultad de Ciencias Físico Matemáticas y Naturales. Instituto Multidisciplinario de Investigaciones Biológicas de San Luis; Argentina Fil: Baldoni, Hector Armando. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - San Luis. Instituto de Matemática Aplicada de San Luis "Prof. Ezio Marchi". Universidad Nacional de San Luis. Facultad de Ciencias Físico, Matemáticas y Naturales. Instituto de Matemática Aplicada de San Luis "Prof. Ezio Marchi"; Argentina. Universidad Nacional de San Luis. Facultad de Química, Bioquímica y Farmacia. Área Química General e Inorgánica; Argentina |
description |
We report a molecular modeling study aimed to locate and provide the full structural characteristics of the exosite binding site of the BACE1. A three-step procedure was followed. In the first stage, we performed blind docking studies on the whole target surface. In a second stage, the mode of binding was further refined by molecular dynamics (MD) simulation. Finally, binding free energy calculations, through the MM-PBSA protocol, were carried out to gain insight into the stability and thermodynamics of the inhibitor located at the selected binding pockets. Twelve binding pockets were identified on the surface of BACE1 by blind docking studies. The calculations of binding free energies for the 12 complexes show that van der Waals interactions dominate the mode of binding of these complexes. The best ranked complex shows that residues Glu255-Pro258, Phe261, Gly264-Ala272, Asp311-Ala313, Ser315, and Asp317-Tyr320 are located within ∼6 Å from the INH located at the exosite. The hydrogen bonds formed between the INH peptide, residues Tyr1, Tyr3, and Leu7 with the BACE1 residues Leu267, Cys269, Trp270, Asp311, and Asp 317 can strengthen the binding of the BACE1-INH complex. |
publishDate |
2010 |
dc.date.none.fl_str_mv |
2010-09-23 |
dc.type.none.fl_str_mv |
info:eu-repo/semantics/article info:eu-repo/semantics/publishedVersion http://purl.org/coar/resource_type/c_6501 info:ar-repo/semantics/articulo |
format |
article |
status_str |
publishedVersion |
dc.identifier.none.fl_str_mv |
http://hdl.handle.net/11336/141177 Gutierrez, Lucas Joel; Enriz, Ricardo Daniel; Baldoni, Hector Armando; Structural and thermodynamic characteristics of the exosite binding pocket on the human BACE1: A molecular modeling approach; American Chemical Society; Journal of Physical Chemistry A; 114; 37; 23-9-2010; 10261-10269 1089-5639 1520-5215 CONICET Digital CONICET |
url |
http://hdl.handle.net/11336/141177 |
identifier_str_mv |
Gutierrez, Lucas Joel; Enriz, Ricardo Daniel; Baldoni, Hector Armando; Structural and thermodynamic characteristics of the exosite binding pocket on the human BACE1: A molecular modeling approach; American Chemical Society; Journal of Physical Chemistry A; 114; 37; 23-9-2010; 10261-10269 1089-5639 1520-5215 CONICET Digital CONICET |
dc.language.none.fl_str_mv |
eng |
language |
eng |
dc.relation.none.fl_str_mv |
info:eu-repo/semantics/altIdentifier/url/https://pubs.acs.org/doi/10.1021/jp104983a info:eu-repo/semantics/altIdentifier/doi/10.1021/jp104983a |
dc.rights.none.fl_str_mv |
info:eu-repo/semantics/openAccess https://creativecommons.org/licenses/by-nc-sa/2.5/ar/ |
eu_rights_str_mv |
openAccess |
rights_invalid_str_mv |
https://creativecommons.org/licenses/by-nc-sa/2.5/ar/ |
dc.format.none.fl_str_mv |
application/pdf application/pdf application/pdf application/pdf |
dc.publisher.none.fl_str_mv |
American Chemical Society |
publisher.none.fl_str_mv |
American Chemical Society |
dc.source.none.fl_str_mv |
reponame:CONICET Digital (CONICET) instname:Consejo Nacional de Investigaciones Científicas y Técnicas |
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CONICET Digital (CONICET) |
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CONICET Digital (CONICET) |
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Consejo Nacional de Investigaciones Científicas y Técnicas |
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CONICET Digital (CONICET) - Consejo Nacional de Investigaciones Científicas y Técnicas |
repository.mail.fl_str_mv |
dasensio@conicet.gov.ar; lcarlino@conicet.gov.ar |
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1844613880105402368 |
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13.070432 |