Ligand Uptake Modulation by Internal Water Molecules and Hydrophobic Cavities in Hemoglobins

Autores
Bustamante, Juan Pablo; Abbruzzetti, Stefania; Marcelli, Agnese; Gauto, Diego Fernando; Boechi, Leonardo; Bonamore, Alessandra; Boffi, Alberto; Bruno, Stefano; Feis, Alessandro; Foggi, Paolo; Estrin, Dario Ariel; Viappiani, Cristiano
Año de publicación
2014
Idioma
inglés
Tipo de recurso
artículo
Estado
versión publicada
Descripción
Internal water molecules play an active role in ligand uptake regulation, since displacement of retained water molecules from protein surfaces or cavities by incoming ligands can promote favorable or disfavorable effects over the global binding process. Detection of these water molecules by X-ray crystallography is difficult given their positional disorder and low occupancy. In this work, we employ a combination of molecular dynamics simulations and ligand rebinding over a broad time range to shed light into the role of water molecules in ligand migration and binding. Computational studies on the unliganded structure of the thermostable truncated hemoglobin from Thermobifida fusca (Tf-trHbO) show that a water molecule is in the vicinity of the iron heme, stabilized by WG8 with the assistance of YCD1, exerting a steric hindrance for binding of an exogenous ligand. Mutation of WG8 to F results in a significantly lower stabilization of this water molecule and in subtle dynamical structural changes that favor ligand binding, as observed experimentally. Water is absent from the fully hydrophobic distal cavity of the triple mutant YB10F-YCD1F-WG8F (3F), due to the lack of residues capable of stabilizing it nearby the heme. In agreement with these effects on the barriers for ligand rebinding, over 97% of the photodissociated ligands are rebound within a few nanoseconds in the 3F mutant case. Our results demonstrate the specific involvement of water molecules in shaping the energetic barriers for ligand migration and binding.
Fil: Bustamante, Juan Pablo. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Ciudad Universitaria. Instituto de Química, Física de los Materiales, Medioambiente y Energía. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales. Instituto de Química, Física de los Materiales, Medioambiente y Energía; Argentina
Fil: Abbruzzetti, Stefania. Università di Parma; Italia
Fil: Marcelli, Agnese. European Laboratory for Non-linear Spectroscopy; Italia
Fil: Gauto, Diego Fernando. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Ciudad Universitaria. Instituto de Química, Física de los Materiales, Medioambiente y Energía. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales. Instituto de Química, Física de los Materiales, Medioambiente y Energía; Argentina
Fil: Boechi, Leonardo. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales. Instituto de Cálculo; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina
Fil: Bonamore, Alessandra. Instituto de Investigaciones Universitarias Roma la Sapienza; Italia
Fil: Boffi, Alberto. Instituto de Investigaciones Universitarias Roma la Sapienza; Italia
Fil: Bruno, Stefano. Università di Parma; Italia
Fil: Feis, Alessandro. Universita Degli Studi Di Firenze; Italia
Fil: Foggi, Paolo. Università di Perugia; Italia. INO-CNR; Italia
Fil: Estrin, Dario Ariel. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Ciudad Universitaria. Instituto de Química, Física de los Materiales, Medioambiente y Energía. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales. Instituto de Química, Física de los Materiales, Medioambiente y Energía; Argentina
Fil: Viappiani, Cristiano. Università di Parma; Italia
Materia
Truncated Hemoglobin
Ligand Migration
Molecular Dynamics
Nivel de accesibilidad
acceso abierto
Condiciones de uso
https://creativecommons.org/licenses/by-nc-sa/2.5/ar/
Repositorio
CONICET Digital (CONICET)
Institución
Consejo Nacional de Investigaciones Científicas y Técnicas
OAI Identificador
oai:ri.conicet.gov.ar:11336/31289
Acceder
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oai_identifier_str oai:ri.conicet.gov.ar:11336/31289
network_acronym_str CONICETDig
repository_id_str 3498
network_name_str CONICET Digital (CONICET)
spelling Ligand Uptake Modulation by Internal Water Molecules and Hydrophobic Cavities in HemoglobinsBustamante, Juan PabloAbbruzzetti, StefaniaMarcelli, AgneseGauto, Diego FernandoBoechi, LeonardoBonamore, AlessandraBoffi, AlbertoBruno, StefanoFeis, AlessandroFoggi, PaoloEstrin, Dario ArielViappiani, CristianoTruncated HemoglobinLigand MigrationMolecular Dynamicshttps://purl.org/becyt/ford/1.6https://purl.org/becyt/ford/1Internal water molecules play an active role in ligand uptake regulation, since displacement of retained water molecules from protein surfaces or cavities by incoming ligands can promote favorable or disfavorable effects over the global binding process. Detection of these water molecules by X-ray crystallography is difficult given their positional disorder and low occupancy. In this work, we employ a combination of molecular dynamics simulations and ligand rebinding over a broad time range to shed light into the role of water molecules in ligand migration and binding. Computational studies on the unliganded structure of the thermostable truncated hemoglobin from Thermobifida fusca (Tf-trHbO) show that a water molecule is in the vicinity of the iron heme, stabilized by WG8 with the assistance of YCD1, exerting a steric hindrance for binding of an exogenous ligand. Mutation of WG8 to F results in a significantly lower stabilization of this water molecule and in subtle dynamical structural changes that favor ligand binding, as observed experimentally. Water is absent from the fully hydrophobic distal cavity of the triple mutant YB10F-YCD1F-WG8F (3F), due to the lack of residues capable of stabilizing it nearby the heme. In agreement with these effects on the barriers for ligand rebinding, over 97% of the photodissociated ligands are rebound within a few nanoseconds in the 3F mutant case. Our results demonstrate the specific involvement of water molecules in shaping the energetic barriers for ligand migration and binding.Fil: Bustamante, Juan Pablo. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Ciudad Universitaria. Instituto de Química, Física de los Materiales, Medioambiente y Energía. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales. Instituto de Química, Física de los Materiales, Medioambiente y Energía; ArgentinaFil: Abbruzzetti, Stefania. Università di Parma; ItaliaFil: Marcelli, Agnese. European Laboratory for Non-linear Spectroscopy; ItaliaFil: Gauto, Diego Fernando. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Ciudad Universitaria. Instituto de Química, Física de los Materiales, Medioambiente y Energía. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales. Instituto de Química, Física de los Materiales, Medioambiente y Energía; ArgentinaFil: Boechi, Leonardo. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales. Instituto de Cálculo; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; ArgentinaFil: Bonamore, Alessandra. Instituto de Investigaciones Universitarias Roma la Sapienza; ItaliaFil: Boffi, Alberto. Instituto de Investigaciones Universitarias Roma la Sapienza; ItaliaFil: Bruno, Stefano. Università di Parma; ItaliaFil: Feis, Alessandro. Universita Degli Studi Di Firenze; ItaliaFil: Foggi, Paolo. Università di Perugia; Italia. INO-CNR; ItaliaFil: Estrin, Dario Ariel. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Ciudad Universitaria. Instituto de Química, Física de los Materiales, Medioambiente y Energía. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales. Instituto de Química, Física de los Materiales, Medioambiente y Energía; ArgentinaFil: Viappiani, Cristiano. Università di Parma; ItaliaAmerican Chemical Society2014-01info:eu-repo/semantics/articleinfo:eu-repo/semantics/publishedVersionhttp://purl.org/coar/resource_type/c_6501info:ar-repo/semantics/articuloapplication/pdfapplication/pdfapplication/pdfapplication/pdfapplication/pdfhttp://hdl.handle.net/11336/31289Viappiani, Cristiano; Estrin, Dario Ariel; Foggi, Paolo; Feis, Alessandro; Bruno, Stefano; Boffi, Alberto; et al.; Ligand Uptake Modulation by Internal Water Molecules and Hydrophobic Cavities in Hemoglobins; American Chemical Society; Journal of Physical Chemistry B; 118; 5; 1-2014; 1234-12451520-6106CONICET DigitalCONICETenginfo:eu-repo/semantics/altIdentifier/doi/10.1021/jp410724zinfo:eu-repo/semantics/altIdentifier/url/http://pubs.acs.org/doi/10.1021/jp410724zinfo:eu-repo/semantics/openAccesshttps://creativecommons.org/licenses/by-nc-sa/2.5/ar/reponame:CONICET Digital (CONICET)instname:Consejo Nacional de Investigaciones Científicas y Técnicas2025-10-15T15:45:29Zoai:ri.conicet.gov.ar:11336/31289instacron: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:34982025-10-15 15:45:30.167CONICET Digital (CONICET) - Consejo Nacional de Investigaciones Científicas y Técnicasfalse
dc.title.none.fl_str_mv Ligand Uptake Modulation by Internal Water Molecules and Hydrophobic Cavities in Hemoglobins
title Ligand Uptake Modulation by Internal Water Molecules and Hydrophobic Cavities in Hemoglobins
spellingShingle Ligand Uptake Modulation by Internal Water Molecules and Hydrophobic Cavities in Hemoglobins
Bustamante, Juan Pablo
Truncated Hemoglobin
Ligand Migration
Molecular Dynamics
title_short Ligand Uptake Modulation by Internal Water Molecules and Hydrophobic Cavities in Hemoglobins
title_full Ligand Uptake Modulation by Internal Water Molecules and Hydrophobic Cavities in Hemoglobins
title_fullStr Ligand Uptake Modulation by Internal Water Molecules and Hydrophobic Cavities in Hemoglobins
title_full_unstemmed Ligand Uptake Modulation by Internal Water Molecules and Hydrophobic Cavities in Hemoglobins
title_sort Ligand Uptake Modulation by Internal Water Molecules and Hydrophobic Cavities in Hemoglobins
dc.creator.none.fl_str_mv Bustamante, Juan Pablo
Abbruzzetti, Stefania
Marcelli, Agnese
Gauto, Diego Fernando
Boechi, Leonardo
Bonamore, Alessandra
Boffi, Alberto
Bruno, Stefano
Feis, Alessandro
Foggi, Paolo
Estrin, Dario Ariel
Viappiani, Cristiano
author Bustamante, Juan Pablo
author_facet Bustamante, Juan Pablo
Abbruzzetti, Stefania
Marcelli, Agnese
Gauto, Diego Fernando
Boechi, Leonardo
Bonamore, Alessandra
Boffi, Alberto
Bruno, Stefano
Feis, Alessandro
Foggi, Paolo
Estrin, Dario Ariel
Viappiani, Cristiano
author_role author
author2 Abbruzzetti, Stefania
Marcelli, Agnese
Gauto, Diego Fernando
Boechi, Leonardo
Bonamore, Alessandra
Boffi, Alberto
Bruno, Stefano
Feis, Alessandro
Foggi, Paolo
Estrin, Dario Ariel
Viappiani, Cristiano
author2_role author
author
author
author
author
author
author
author
author
author
author
dc.subject.none.fl_str_mv Truncated Hemoglobin
Ligand Migration
Molecular Dynamics
topic Truncated Hemoglobin
Ligand Migration
Molecular Dynamics
purl_subject.fl_str_mv https://purl.org/becyt/ford/1.6
https://purl.org/becyt/ford/1
dc.description.none.fl_txt_mv Internal water molecules play an active role in ligand uptake regulation, since displacement of retained water molecules from protein surfaces or cavities by incoming ligands can promote favorable or disfavorable effects over the global binding process. Detection of these water molecules by X-ray crystallography is difficult given their positional disorder and low occupancy. In this work, we employ a combination of molecular dynamics simulations and ligand rebinding over a broad time range to shed light into the role of water molecules in ligand migration and binding. Computational studies on the unliganded structure of the thermostable truncated hemoglobin from Thermobifida fusca (Tf-trHbO) show that a water molecule is in the vicinity of the iron heme, stabilized by WG8 with the assistance of YCD1, exerting a steric hindrance for binding of an exogenous ligand. Mutation of WG8 to F results in a significantly lower stabilization of this water molecule and in subtle dynamical structural changes that favor ligand binding, as observed experimentally. Water is absent from the fully hydrophobic distal cavity of the triple mutant YB10F-YCD1F-WG8F (3F), due to the lack of residues capable of stabilizing it nearby the heme. In agreement with these effects on the barriers for ligand rebinding, over 97% of the photodissociated ligands are rebound within a few nanoseconds in the 3F mutant case. Our results demonstrate the specific involvement of water molecules in shaping the energetic barriers for ligand migration and binding.
Fil: Bustamante, Juan Pablo. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Ciudad Universitaria. Instituto de Química, Física de los Materiales, Medioambiente y Energía. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales. Instituto de Química, Física de los Materiales, Medioambiente y Energía; Argentina
Fil: Abbruzzetti, Stefania. Università di Parma; Italia
Fil: Marcelli, Agnese. European Laboratory for Non-linear Spectroscopy; Italia
Fil: Gauto, Diego Fernando. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Ciudad Universitaria. Instituto de Química, Física de los Materiales, Medioambiente y Energía. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales. Instituto de Química, Física de los Materiales, Medioambiente y Energía; Argentina
Fil: Boechi, Leonardo. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales. Instituto de Cálculo; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina
Fil: Bonamore, Alessandra. Instituto de Investigaciones Universitarias Roma la Sapienza; Italia
Fil: Boffi, Alberto. Instituto de Investigaciones Universitarias Roma la Sapienza; Italia
Fil: Bruno, Stefano. Università di Parma; Italia
Fil: Feis, Alessandro. Universita Degli Studi Di Firenze; Italia
Fil: Foggi, Paolo. Università di Perugia; Italia. INO-CNR; Italia
Fil: Estrin, Dario Ariel. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Ciudad Universitaria. Instituto de Química, Física de los Materiales, Medioambiente y Energía. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales. Instituto de Química, Física de los Materiales, Medioambiente y Energía; Argentina
Fil: Viappiani, Cristiano. Università di Parma; Italia
description Internal water molecules play an active role in ligand uptake regulation, since displacement of retained water molecules from protein surfaces or cavities by incoming ligands can promote favorable or disfavorable effects over the global binding process. Detection of these water molecules by X-ray crystallography is difficult given their positional disorder and low occupancy. In this work, we employ a combination of molecular dynamics simulations and ligand rebinding over a broad time range to shed light into the role of water molecules in ligand migration and binding. Computational studies on the unliganded structure of the thermostable truncated hemoglobin from Thermobifida fusca (Tf-trHbO) show that a water molecule is in the vicinity of the iron heme, stabilized by WG8 with the assistance of YCD1, exerting a steric hindrance for binding of an exogenous ligand. Mutation of WG8 to F results in a significantly lower stabilization of this water molecule and in subtle dynamical structural changes that favor ligand binding, as observed experimentally. Water is absent from the fully hydrophobic distal cavity of the triple mutant YB10F-YCD1F-WG8F (3F), due to the lack of residues capable of stabilizing it nearby the heme. In agreement with these effects on the barriers for ligand rebinding, over 97% of the photodissociated ligands are rebound within a few nanoseconds in the 3F mutant case. Our results demonstrate the specific involvement of water molecules in shaping the energetic barriers for ligand migration and binding.
publishDate 2014
dc.date.none.fl_str_mv 2014-01
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/11336/31289
Viappiani, Cristiano; Estrin, Dario Ariel; Foggi, Paolo; Feis, Alessandro; Bruno, Stefano; Boffi, Alberto; et al.; Ligand Uptake Modulation by Internal Water Molecules and Hydrophobic Cavities in Hemoglobins; American Chemical Society; Journal of Physical Chemistry B; 118; 5; 1-2014; 1234-1245
1520-6106
CONICET Digital
CONICET
url http://hdl.handle.net/11336/31289
identifier_str_mv Viappiani, Cristiano; Estrin, Dario Ariel; Foggi, Paolo; Feis, Alessandro; Bruno, Stefano; Boffi, Alberto; et al.; Ligand Uptake Modulation by Internal Water Molecules and Hydrophobic Cavities in Hemoglobins; American Chemical Society; Journal of Physical Chemistry B; 118; 5; 1-2014; 1234-1245
1520-6106
CONICET Digital
CONICET
dc.language.none.fl_str_mv eng
language eng
dc.relation.none.fl_str_mv info:eu-repo/semantics/altIdentifier/doi/10.1021/jp410724z
info:eu-repo/semantics/altIdentifier/url/http://pubs.acs.org/doi/10.1021/jp410724z
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
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
reponame_str CONICET Digital (CONICET)
collection CONICET Digital (CONICET)
instname_str Consejo Nacional de Investigaciones Científicas y Técnicas
repository.name.fl_str_mv 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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score 13.22299

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