Ligand migration in the apolar tunnel of Cerebratulus lacteus mini-hemoglobin

The large apolar tunnel traversing the mini-hemoglobin from Cerebratulus lacteus (CerHb) has been examined by xray crystallography, ligand binding kinetics, and molecular dynamic simulations. The addition of 10 atm of xenon causes loss of diffraction in wild-type (wt) CerHbO2 crystals, but Leu-86(G1...

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Publicado:	2011
Materias:	Amide side chain Bimolecular rate constants CO Rebinding Heme iron Ligand binding Ligand movement Low energies Molecular dynamic simulations Molecular dynamics simulations Wild types Xenon atoms Amides Computer simulation Crystallography Hemoglobin Internet protocols Molecular dynamics Porphyrins Rate constants Ligands ligand article binding kinetics cell migration Cerebratulus lacteus controlled study crystallization dissociation equilibrium constant gene mutation genetic recombination hydrogen bond ligand binding molecular dynamics Nemertea nonhuman oxidation photolysis priority journal protein conformation thermodynamics X ray crystallography X ray diffraction Animals Computer Simulation Crystallography, X-Ray Heme Hemoglobins Invertebrates Iron Kinetics Models, Molecular Mutation, Missense Protein Structure, Tertiary Thermodynamics Xenon
Acceso en línea:	https://bibliotecadigital.exactas.uba.ar/collection/paper/document/paper_00219258_v286_n7_p5347_Pesce http://hdl.handle.net/20.500.12110/paper_00219258_v286_n7_p5347_Pesce
Aporte de:	Biblioteca Digital - Facultad de Ciencias Exactas y Naturales (UBA) de Universidad de Buenos Aires

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spelling	paper:paper_00219258_v286_n7_p5347_Pesce2023-06-08T14:43:32Z Ligand migration in the apolar tunnel of Cerebratulus lacteus mini-hemoglobin Amide side chain Bimolecular rate constants CO Rebinding Heme iron Ligand binding Ligand movement Low energies Molecular dynamic simulations Molecular dynamics simulations Wild types Xenon atoms Amides Computer simulation Crystallography Hemoglobin Internet protocols Molecular dynamics Porphyrins Rate constants Ligands ligand article binding kinetics cell migration Cerebratulus lacteus controlled study crystallization dissociation equilibrium constant gene mutation genetic recombination hydrogen bond ligand binding molecular dynamics Nemertea nonhuman oxidation photolysis priority journal protein conformation thermodynamics X ray crystallography X ray diffraction Animals Computer Simulation Crystallography, X-Ray Heme Hemoglobins Invertebrates Iron Kinetics Ligands Models, Molecular Mutation, Missense Protein Structure, Tertiary Thermodynamics Xenon Cerebratulus lacteus The large apolar tunnel traversing the mini-hemoglobin from Cerebratulus lacteus (CerHb) has been examined by xray crystallography, ligand binding kinetics, and molecular dynamic simulations. The addition of 10 atm of xenon causes loss of diffraction in wild-type (wt) CerHbO2 crystals, but Leu-86(G12)Ala CerHbO2, which has an increased tunnel volume, stably accommodates two discrete xenon atoms: one adjacent to Leu-86(G12) and another near Ala-55(E18). Molecular dynamics simulations of ligand migration in wt CerHb show a low energy pathway through the apolar tunnel when Leu or Ala, but not Phe or Trp, is present at the 86(G12) position. The addition of 10-15 atm of xenon to solutions of wt CerHbCO and L86A CerHbCO causes 2-3-fold increases in the fraction of geminate ligand recombination, indicating that the bound xenon blocks CO escape. This idea was confirmed by L86F and L86W mutations, which cause even larger increases in the fraction of geminate CO rebinding, 2-5-fold decreases in the bimolecular rate constants for ligand entry, and large increases in the computed energy barriers for ligand movement through the apolar tunnel. Both the addition of xenon to the L86A mutant and oxidation of wt CerHb heme iron cause the appearance of an out Gln-44(E7) conformer, in which the amide side chain points out toward the solvent and appears to lower the barrier for ligand escape through the E7 gate. However, the observed kinetics suggest little entry and escape (≤25%) through the E7 pathway, presumably because the in Gln- 44(E7) conformer is thermodynamically favored. © 2011 by The American Society for Biochemistry and Molecular Biology, Inc. 2011 https://bibliotecadigital.exactas.uba.ar/collection/paper/document/paper_00219258_v286_n7_p5347_Pesce http://hdl.handle.net/20.500.12110/paper_00219258_v286_n7_p5347_Pesce
institution	Universidad de Buenos Aires
institution_str	I-28
repository_str	R-134
collection	Biblioteca Digital - Facultad de Ciencias Exactas y Naturales (UBA)
topic	Amide side chain Bimolecular rate constants CO Rebinding Heme iron Ligand binding Ligand movement Low energies Molecular dynamic simulations Molecular dynamics simulations Wild types Xenon atoms Amides Computer simulation Crystallography Hemoglobin Internet protocols Molecular dynamics Porphyrins Rate constants Ligands ligand article binding kinetics cell migration Cerebratulus lacteus controlled study crystallization dissociation equilibrium constant gene mutation genetic recombination hydrogen bond ligand binding molecular dynamics Nemertea nonhuman oxidation photolysis priority journal protein conformation thermodynamics X ray crystallography X ray diffraction Animals Computer Simulation Crystallography, X-Ray Heme Hemoglobins Invertebrates Iron Kinetics Ligands Models, Molecular Mutation, Missense Protein Structure, Tertiary Thermodynamics Xenon Cerebratulus lacteus
spellingShingle	Amide side chain Bimolecular rate constants CO Rebinding Heme iron Ligand binding Ligand movement Low energies Molecular dynamic simulations Molecular dynamics simulations Wild types Xenon atoms Amides Computer simulation Crystallography Hemoglobin Internet protocols Molecular dynamics Porphyrins Rate constants Ligands ligand article binding kinetics cell migration Cerebratulus lacteus controlled study crystallization dissociation equilibrium constant gene mutation genetic recombination hydrogen bond ligand binding molecular dynamics Nemertea nonhuman oxidation photolysis priority journal protein conformation thermodynamics X ray crystallography X ray diffraction Animals Computer Simulation Crystallography, X-Ray Heme Hemoglobins Invertebrates Iron Kinetics Ligands Models, Molecular Mutation, Missense Protein Structure, Tertiary Thermodynamics Xenon Cerebratulus lacteus Ligand migration in the apolar tunnel of Cerebratulus lacteus mini-hemoglobin
topic_facet	Amide side chain Bimolecular rate constants CO Rebinding Heme iron Ligand binding Ligand movement Low energies Molecular dynamic simulations Molecular dynamics simulations Wild types Xenon atoms Amides Computer simulation Crystallography Hemoglobin Internet protocols Molecular dynamics Porphyrins Rate constants Ligands ligand article binding kinetics cell migration Cerebratulus lacteus controlled study crystallization dissociation equilibrium constant gene mutation genetic recombination hydrogen bond ligand binding molecular dynamics Nemertea nonhuman oxidation photolysis priority journal protein conformation thermodynamics X ray crystallography X ray diffraction Animals Computer Simulation Crystallography, X-Ray Heme Hemoglobins Invertebrates Iron Kinetics Ligands Models, Molecular Mutation, Missense Protein Structure, Tertiary Thermodynamics Xenon Cerebratulus lacteus
description	The large apolar tunnel traversing the mini-hemoglobin from Cerebratulus lacteus (CerHb) has been examined by xray crystallography, ligand binding kinetics, and molecular dynamic simulations. The addition of 10 atm of xenon causes loss of diffraction in wild-type (wt) CerHbO2 crystals, but Leu-86(G12)Ala CerHbO2, which has an increased tunnel volume, stably accommodates two discrete xenon atoms: one adjacent to Leu-86(G12) and another near Ala-55(E18). Molecular dynamics simulations of ligand migration in wt CerHb show a low energy pathway through the apolar tunnel when Leu or Ala, but not Phe or Trp, is present at the 86(G12) position. The addition of 10-15 atm of xenon to solutions of wt CerHbCO and L86A CerHbCO causes 2-3-fold increases in the fraction of geminate ligand recombination, indicating that the bound xenon blocks CO escape. This idea was confirmed by L86F and L86W mutations, which cause even larger increases in the fraction of geminate CO rebinding, 2-5-fold decreases in the bimolecular rate constants for ligand entry, and large increases in the computed energy barriers for ligand movement through the apolar tunnel. Both the addition of xenon to the L86A mutant and oxidation of wt CerHb heme iron cause the appearance of an out Gln-44(E7) conformer, in which the amide side chain points out toward the solvent and appears to lower the barrier for ligand escape through the E7 gate. However, the observed kinetics suggest little entry and escape (≤25%) through the E7 pathway, presumably because the in Gln- 44(E7) conformer is thermodynamically favored. © 2011 by The American Society for Biochemistry and Molecular Biology, Inc.
title	Ligand migration in the apolar tunnel of Cerebratulus lacteus mini-hemoglobin
title_short	Ligand migration in the apolar tunnel of Cerebratulus lacteus mini-hemoglobin
title_full	Ligand migration in the apolar tunnel of Cerebratulus lacteus mini-hemoglobin
title_fullStr	Ligand migration in the apolar tunnel of Cerebratulus lacteus mini-hemoglobin
title_full_unstemmed	Ligand migration in the apolar tunnel of Cerebratulus lacteus mini-hemoglobin
title_sort	ligand migration in the apolar tunnel of cerebratulus lacteus mini-hemoglobin
publishDate	2011
url	https://bibliotecadigital.exactas.uba.ar/collection/paper/document/paper_00219258_v286_n7_p5347_Pesce http://hdl.handle.net/20.500.12110/paper_00219258_v286_n7_p5347_Pesce
_version_	1768543736499798016

Ligand migration in the apolar tunnel of Cerebratulus lacteus mini-hemoglobin

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