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
- Institución
- Consejo Nacional de Investigaciones Científicas y Técnicas
- OAI Identificador
- oai:ri.conicet.gov.ar:11336/31289
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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 Técnicas2025-09-29T10:46:54Zoai: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:34982025-09-29 10:46:54.395CONICET 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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1844614511649095680 |
score |
13.070432 |