Competition with Xenon Elicits Ligand Migration and Escape Pathways in Myoglobin

Tétreau, Catherine; Blouquit, Y.; Novikov, Eugene; Quiniou, É.; Lavalette, Daniel

doi:10.1016/s0006-3495(04)74120-x

Cited by 59 publications

(80 citation statements)

References 49 publications

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“…However, escape can be quantified provided it competes with some rebinding process. Experimental evidence for the presence of two escape pathways was reported only recently in Mb, but this case was rather exceptional (Tetreau et al 2004). MD simulations provide the adequate and complementary alternative to the description of these processes.…”

Section: Ligand Escape From the Proteinmentioning

confidence: 92%

“…Finally, the identified CO migration pathways provide a consistent interpretation of the experimental rebinding kinetics. (Srajer et al 2001;Bourgeois et al 2003;Schotte et al 2003;Hummer et al 2004), cryocrystallography (Brunori et al 2000Chu et al 2000;Ostermann et al 2000;Schlichting 2000), spectroscopy (Engler et al 2000;Lamb et al 2002;Nienhaus et al 2002;Kriegl et al 2003), kinetic competition experiments with xenon (Scott and Gibson 1997;Scott et al 2001; Nienhaus et al 2003a,b;Tetreau et al 2004, and molecular dynamics (MD) simulations (Elber and Karplus 1990;Carlson et al 1996;Meller and Elber 1998;Amara et al 2001;Mouawad et al 2005). Article published online ahead of print.…”

Section: Introductionmentioning

confidence: 99%

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CO migration pathways in cytochrome P450_cam studied by molecular dynamics simulations

Mouawad¹,

Tétreau²,

Abdel‐Azeim³

et al. 2007

Protein Science

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Previous laser flash photolysis investigations between 100 and 300 K have shown that the kinetics of CO rebinding with cytochrome P450 cam (camphor) consist of up to four different processes revealing a complex internal dynamics after ligand dissociation. In the present work, molecular dynamics simulations were undertaken on the ternary complex P450 cam (cam)(CO) to explore the CO migration pathways, monitor the internal cavities of the protein, and localize the CO docking sites. One trajectory of 1 nsec with the protein in a water box and 36 trajectories of 1 nsec in the vacuum were calculated. In each trajectory, the protein contained only one CO ligand on which no constraints were applied. The simulations were performed at 200, 300, and 320 K. The results indicate the presence of seven CO docking sites, mainly hydrophobic, located in the same moiety of the protein. Two of them coincide with xenon binding sites identified by crystallography. The protein matrix exhibits eight persistent internal cavities, four of which corresponding to the ligand docking sites. In addition, it was observed that water molecules entering the protein were mainly attracted into the polar pockets, far away from the CO docking sites. Finally, the identified CO migration pathways provide a consistent interpretation of the experimental rebinding kinetics. (Srajer et al. 2001;Bourgeois et al. 2003;Schotte et al. 2003;Hummer et al. 2004), cryocrystallography (Brunori et al. 2000Chu et al. 2000;Ostermann et al. 2000;Schlichting 2000), spectroscopy (Engler et al. 2000;Lamb et al. 2002;Nienhaus et al. 2002;Kriegl et al. 2003), kinetic competition experiments with xenon (Scott and Gibson 1997;Scott et al. 2001; Nienhaus et al. 2003a,b;Tetreau et al. 2004, and molecular dynamics (MD) simulations (Elber and Karplus 1990;Carlson et al. 1996;Meller and Elber 1998;Amara et al. 2001;Mouawad et al. 2005). Article published online ahead of print. Article and publication date are at

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Section: Ligand Escape From the Proteinmentioning

confidence: 92%

Section: Introductionmentioning

confidence: 99%

CO migration pathways in cytochrome P450_cam studied by molecular dynamics simulations

Mouawad¹,

Tétreau²,

Abdel‐Azeim³

et al. 2007

Protein Science

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“…Initially, the spectroscopic and theoretical work favored the barrier raising relaxation model. Subsequently, the unambiguous demonstration that dissociated CO could access packing defect (Xe cavities) within the protein (Schoenborn et al, 1965;Tilton et al, 1984) provided compelling support for the slow rebinding docking site models (Hartmann et al, 1996;Scott and Gibson, 1997; Brunori et al, 1999;Brunori et al, 2000;Ostermann et al, 2000;Scott et al, 2000;Srajer et al, 2001;Bourgeois et al, 2003;Kriegl et al, 2003;Nienhaus et al, 2003b;Nienhaus et al, 2003a;Schotte et al, 2003;Lamb et al, 2004;Tetreau et al, 2004); however, these results do not preclude a significant role for a barrier increase via conformational relaxation. …”

mentioning

confidence: 99%

“…This phase is what is typically observed (Austin et al, 1973;Austin et al, 1975)for recombination at very low cryogenic temperature conditions (< 100 K). Two kinetic sub-phases have been identified (Tetreau et al, 2004;Dantsker et al, 2005a;Dantsker et al, 2005b)which have been referred to as: B→A and B′→A. These two phases are attributed to rebinding from sites within the distal heme pocket that are close to the heme-iron and removed from the heme-iron respectively.…”

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confidence: 99%

Ligand recombination and a hierarchy of solvent slaved dynamics: The origin of kinetic phases in hemeproteins

Samuni

Dantsker

Roche

et al. 2007

Gene

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Ligand recombination studies play a central role both for characterizing different hemeproteins and there conformational states but also for probing fundamental biophysical processes. Consequently, there is great importance to providing a foundation from which one can understand the physical processes that give rise to and modulate the large range of kinetic patterns associated with ligand recombination in myoglobins and hemoglobins. In this work, an overview of cryogenic and solution phase recombination phenomena for COMb is first reviewed and then a new paradigm is presented for analyzing the temperature and viscosity dependent features of kinetic traces in terms of multiple phases that reflect which tier(s) of solvent-slaved protein dynamics is(are) operative on the photoproduct population during the time course of the measurement. This approach allows for facile inclusion of both ligand diffusion among accessible cavities and conformational relaxation effects. The concepts are illustrated using kinetic traces and MEM populations derived from the CO recombination process for wild type and mutant myoglobins either in sol-gel matrices bathed in glycerol or in trehalose derived glassy matrices. Keywords myoglobin; carbonmonoxide; sol-gel; trehalose; geminate recombination; Xe cavities Ligand recombinationStudies utilizing ligand recombination subsequent to photodissociation continue to provide basic insight into the functional properties of the many varieties of hemoglobin and myoglobin like molecules that are found through out the animal and plant worlds. Such studies are significant for several reasons all of which stem from the sensitivity of the recombination process to global structure, site specific effects and dynamics. Ligand recombination data at ambient temperatures are often useful in establishing potential functions of a newly described hemeproteins as well as routinely being used in exploring structure-function correlations in well characterized molecules such as human hemoglobin and mammalian myoglobins. Ligand recombination in myoglobin in particular has provided biophysics with a process that has allowed for dramatic advances in understanding: i) protein dynamics, ii) the role of protein dynamics in modulating protein reactivity and iii) the interplay between the dynamical properties of the protein and the surrounding solvent. Despite the heavy focus on understanding Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. NIH Public Access Author ManuscriptGene. Author manuscript; available in PMC 2008 August 15. Published in final edited form as:Gene. 200...

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“…As recently reviewed by Elber (11), molecular dynamics simulations and other computational approaches have almost uniformly suggested that there are multiple routes for ligand entry into and escape from the active sites of hemoglobins and myoglobins (12)(13)(14)(15)(16)(17)(18)(19)(20)(21)(22)(23)(24)(25)(26)(27). Many of these pathways are coincident with apolar cavities, which have been identified as xenon docking sites (16, 17, 28 -30).…”

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confidence: 99%

Blocking the Gate to Ligand Entry in Human Hemoglobin

Birukou

Soman

Olson

2011

Journal of Biological Chemistry

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His(E7) to Trp replacements inHemoglobins represent a very diverse protein family with members occurring in all six kingdoms of life (1). The functions of these proteins differ significantly, ranging from oxygen storage and transport, NO dioxygenation, and nitrite reduction to sensing intracellular levels of diatomic gases for transcriptional regulation and chemotaxis (2). The central chemical events for these functions are movement of ligands into the distal portion of the heme pocket, internal bond formation with the heme iron, and electrostatic stabilization or steric hindrance of the bound ligand by surrounding active site amino acids. Although the quantum mechanical details of bond formation remain to be resolved, there is general agreement on the biophysical mechanisms governing steric hindrance and hydrogen bonding between amino acid side chains and the bound ligand (3-10). In contrast, the pathways for ligands movement from solvent through the protein and into the active site are still under debate.As recently reviewed by Elber (11), molecular dynamics simulations and other computational approaches have almost uniformly suggested that there are multiple routes for ligand entry into and escape from the active sites of hemoglobins and myoglobins (12-27). Many of these pathways are coincident with apolar cavities, which have been identified as xenon docking sites (16, 17, 28 -30). However, as also pointed out by Elber (11), there is little or no direct experimental evidence in support of multiple pathways (31, 32). In the cases of mammalian myoglobins, human hemoglobin, and HbI from Scapharca inaequivalvis, almost all of the experimental evidence suggests that Ն75% of ligands enter and exit the distal pocket through a transient channel between the heme propionates, which is produced by outward rotation of the distal histidine (His(E7)). 2Although ligands do migrate into internal cavities immediately after photodissociation, they appear to return to the distal pocket and escape through the E7 gate (33-41).The structures of the active sites and the E7 channels in Mb and the subunits of human HbA are very similar, and thus analogous mechanisms for ligand binding are inferred. Until very recently, there were little experimental and computational data regarding the pathways of ligand migration into HbA. Mouawad et al. (15) observed the formation of transient cavities in the ␣ and ␤ subunits of human HbA during simulations of the T to R conformational change and postulated these cavities could allow ligands to diffuse through the globin matrix. Sottini et al. (16,17) used molecular modeling approaches to find potential xenon binding cavities in human HbA and suggested that ligands could use these apolar voids as pathways to enter or escape the active site. Savino et al. (30) reported crystal structures of Tyr(B10)/Gln(E7) deoxyHbA with xenon atoms partially occupying the sites identified in molecular modeling experiments. Thus, if only the theoretical and structural litera-* This work was supported, in whole or...

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Competition with Xenon Elicits Ligand Migration and Escape Pathways in Myoglobin

Cited by 59 publications

References 49 publications

CO migration pathways in cytochrome P450_cam studied by molecular dynamics simulations

CO migration pathways in cytochrome P450_cam studied by molecular dynamics simulations

Ligand recombination and a hierarchy of solvent slaved dynamics: The origin of kinetic phases in hemeproteins

Blocking the Gate to Ligand Entry in Human Hemoglobin

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Competition with Xenon Elicits Ligand Migration and Escape Pathways in Myoglobin

Cited by 59 publications

References 49 publications

CO migration pathways in cytochrome P450cam studied by molecular dynamics simulations

CO migration pathways in cytochrome P450cam studied by molecular dynamics simulations

Ligand recombination and a hierarchy of solvent slaved dynamics: The origin of kinetic phases in hemeproteins

Blocking the Gate to Ligand Entry in Human Hemoglobin

Contact Info

Product

Resources

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CO migration pathways in cytochrome P450_cam studied by molecular dynamics simulations

CO migration pathways in cytochrome P450_cam studied by molecular dynamics simulations