Ligand uptake modulation by internal water molecules and hydrophobic cavities in hemoglobins

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 cr...

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Autores principales:	Bustamante, Juan Pablo, Gauto, Diego Fernando, Boechi, Leonardo, Estrin, Dario Ariel
Publicado:	2014
Materias:	Computational studies Energetic barriers Exogenous ligands Hydrophobic cavities Molecular dynamics simulations Positional disorder Thermobifida fusca Truncated hemoglobins Hemoglobin Hydrophobicity Molecular dynamics Molecules Porphyrins X ray crystallography Ligands carbon monoxide hemoglobin ligand truncated hemoglobin water article chemical phenomena chemistry kinetics metabolism protein binding protein tertiary structure thermodynamics Carbon Monoxide Hemoglobins Hydrophobic and Hydrophilic Interactions Kinetics Protein Binding Protein Structure, Tertiary Thermodynamics Truncated Hemoglobins Water
Acceso en línea:	https://bibliotecadigital.exactas.uba.ar/collection/paper/document/paper_15206106_v118_n5_p1234_Bustamante http://hdl.handle.net/20.500.12110/paper_15206106_v118_n5_p1234_Bustamante
Aporte de:	Biblioteca Digital - Facultad de Ciencias Exactas y Naturales (UBA) de Universidad de Buenos Aires

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spelling	paper:paper_15206106_v118_n5_p1234_Bustamante2023-06-08T16:19:09Z Ligand uptake modulation by internal water molecules and hydrophobic cavities in hemoglobins Bustamante, Juan Pablo Gauto, Diego Fernando Boechi, Leonardo Estrin, Dario Ariel Computational studies Energetic barriers Exogenous ligands Hydrophobic cavities Molecular dynamics simulations Positional disorder Thermobifida fusca Truncated hemoglobins Hemoglobin Hydrophobicity Molecular dynamics Molecules Porphyrins X ray crystallography Ligands carbon monoxide hemoglobin ligand truncated hemoglobin water article chemical phenomena chemistry kinetics metabolism protein binding protein tertiary structure thermodynamics Carbon Monoxide Hemoglobins Hydrophobic and Hydrophilic Interactions Kinetics Ligands Protein Binding Protein Structure, Tertiary Thermodynamics Truncated Hemoglobins Water 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. © 2014 American Chemical Society. Fil:Bustamante, J.P. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales; Argentina. Fil:Gauto, D. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales; Argentina. Fil:Boechi, L. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales; Argentina. Fil:Estrin, D.A. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales; Argentina. 2014 https://bibliotecadigital.exactas.uba.ar/collection/paper/document/paper_15206106_v118_n5_p1234_Bustamante http://hdl.handle.net/20.500.12110/paper_15206106_v118_n5_p1234_Bustamante
institution	Universidad de Buenos Aires
institution_str	I-28
repository_str	R-134
collection	Biblioteca Digital - Facultad de Ciencias Exactas y Naturales (UBA)
topic	Computational studies Energetic barriers Exogenous ligands Hydrophobic cavities Molecular dynamics simulations Positional disorder Thermobifida fusca Truncated hemoglobins Hemoglobin Hydrophobicity Molecular dynamics Molecules Porphyrins X ray crystallography Ligands carbon monoxide hemoglobin ligand truncated hemoglobin water article chemical phenomena chemistry kinetics metabolism protein binding protein tertiary structure thermodynamics Carbon Monoxide Hemoglobins Hydrophobic and Hydrophilic Interactions Kinetics Ligands Protein Binding Protein Structure, Tertiary Thermodynamics Truncated Hemoglobins Water
spellingShingle	Computational studies Energetic barriers Exogenous ligands Hydrophobic cavities Molecular dynamics simulations Positional disorder Thermobifida fusca Truncated hemoglobins Hemoglobin Hydrophobicity Molecular dynamics Molecules Porphyrins X ray crystallography Ligands carbon monoxide hemoglobin ligand truncated hemoglobin water article chemical phenomena chemistry kinetics metabolism protein binding protein tertiary structure thermodynamics Carbon Monoxide Hemoglobins Hydrophobic and Hydrophilic Interactions Kinetics Ligands Protein Binding Protein Structure, Tertiary Thermodynamics Truncated Hemoglobins Water Bustamante, Juan Pablo Gauto, Diego Fernando Boechi, Leonardo Estrin, Dario Ariel Ligand uptake modulation by internal water molecules and hydrophobic cavities in hemoglobins
topic_facet	Computational studies Energetic barriers Exogenous ligands Hydrophobic cavities Molecular dynamics simulations Positional disorder Thermobifida fusca Truncated hemoglobins Hemoglobin Hydrophobicity Molecular dynamics Molecules Porphyrins X ray crystallography Ligands carbon monoxide hemoglobin ligand truncated hemoglobin water article chemical phenomena chemistry kinetics metabolism protein binding protein tertiary structure thermodynamics Carbon Monoxide Hemoglobins Hydrophobic and Hydrophilic Interactions Kinetics Ligands Protein Binding Protein Structure, Tertiary Thermodynamics Truncated Hemoglobins Water
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. © 2014 American Chemical Society.
author	Bustamante, Juan Pablo Gauto, Diego Fernando Boechi, Leonardo Estrin, Dario Ariel
author_facet	Bustamante, Juan Pablo Gauto, Diego Fernando Boechi, Leonardo Estrin, Dario Ariel
author_sort	Bustamante, Juan Pablo
title	Ligand uptake modulation by internal water molecules and hydrophobic cavities in hemoglobins
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
publishDate	2014
url	https://bibliotecadigital.exactas.uba.ar/collection/paper/document/paper_15206106_v118_n5_p1234_Bustamante http://hdl.handle.net/20.500.12110/paper_15206106_v118_n5_p1234_Bustamante
work_keys_str_mv	AT bustamantejuanpablo liganduptakemodulationbyinternalwatermoleculesandhydrophobiccavitiesinhemoglobins AT gautodiegofernando liganduptakemodulationbyinternalwatermoleculesandhydrophobiccavitiesinhemoglobins AT boechileonardo liganduptakemodulationbyinternalwatermoleculesandhydrophobiccavitiesinhemoglobins AT estrindarioariel liganduptakemodulationbyinternalwatermoleculesandhydrophobiccavitiesinhemoglobins
_version_	1768541767986053120

Ligand uptake modulation by internal water molecules and hydrophobic cavities in hemoglobins

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