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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todo:paper_15206106_v118_n5_p1234_Bustamante2023-10-03T16:20:28Z Ligand uptake modulation by internal water molecules and hydrophobic cavities in hemoglobins Bustamante, J.P. Abbruzzetti, S. Marcelli, A. Gauto, D. Boechi, L. Bonamore, A. Boffi, A. Bruno, S. Feis, A. Foggi, P. Estrin, D.A. Viappiani, C. 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. JOUR info:eu-repo/semantics/openAccess http://creativecommons.org/licenses/by/2.5/ar 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, J.P. Abbruzzetti, S. Marcelli, A. Gauto, D. Boechi, L. Bonamore, A. Boffi, A. Bruno, S. Feis, A. Foggi, P. Estrin, D.A. Viappiani, C. 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. |
| format |
JOUR |
| author |
Bustamante, J.P. Abbruzzetti, S. Marcelli, A. Gauto, D. Boechi, L. Bonamore, A. Boffi, A. Bruno, S. Feis, A. Foggi, P. Estrin, D.A. Viappiani, C. |
| author_facet |
Bustamante, J.P. Abbruzzetti, S. Marcelli, A. Gauto, D. Boechi, L. Bonamore, A. Boffi, A. Bruno, S. Feis, A. Foggi, P. Estrin, D.A. Viappiani, C. |
| author_sort |
Bustamante, J.P. |
| 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 |
| url |
http://hdl.handle.net/20.500.12110/paper_15206106_v118_n5_p1234_Bustamante |
| work_keys_str_mv |
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