Ligand diffusion in globins: simulations versus experiment

Elber, Ron

doi:10.1016/j.sbi.2010.01.002

Cited by 78 publications

(62 citation statements)

References 56 publications

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“…More than 50 years of research have culminated in Mb becoming one of the most studied proteins in the field of structural biology (4). The histidine gate hypothesis and the role played by alternative ligand migration paths have been examined in detail by both experimental and theoretical methodologies but are still surrounded by controversy (5). It would be impractical to describe all the available data, and instead, we will attempt to summarize the key observations and discrepancies.…”

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Hydrophobic Effect Drives Oxygen Uptake in Myoglobin via Histidine E7

Boechi

Arrar

Martí

et al. 2013

Journal of Biological Chemistry

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Background:The distal histidine in myoglobin is thought to act as a gate regulating oxygen uptake. Results:Neither the open nor closed conformation hinders oxygen uptake; a hydrophobic site is more apparent in the open conformation. Conclusion:The driving force for ligand uptake is the hydrophobic effect. Significance: This amplifies our understanding of the mechanisms through which proteins regulate ligand uptake.

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confidence: 99%

Hydrophobic Effect Drives Oxygen Uptake in Myoglobin via Histidine E7

Boechi

Arrar

Martí

et al. 2013

Journal of Biological Chemistry

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“…Previous studies have characterized gas diffusion in myoglobin (16)(17)(18)(19), (reviewed in ref. 20), lipoxygenase (21), flavin-containing monooxygenase (22) and oxidases (22,23) (reviewed in ref. 24), and hydrogenase (25)(26)(27)(28).…”

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confidence: 99%

Mechanistic insight into the blocking of CO diffusion in [NiFe]-hydrogenase mutants through multiscale simulation

Wang

Blumberger

2012

Proc. Natl. Acad. Sci. U.S.A.

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[NiFe]-hydrogenases are fascinating biological catalysts with potential application in biofuel cells. However, a severe problem in practical application is the strong sensitivity of hydrogenase to gaseous inhibitor molecules such as CO and O 2 . Recently, a number of successful protein engineering studies have been reported that aimed at lowering the access of diatomic inhibitors to the active site pocket, but the molecular mechanism conferring increased resistance remained unclear. Here we use a multiscale simulation approach combining molecular dynamics with a master equation formalism to explain the steady drop in CO diffusion rate observed for the mutants V74M L122A, V74M L122M, and V74M of Desulfovibrio fructosovorans [NiFe]-hydrogenase. We find that diffusion in these variants is controlled by two gates, one between residues 74 and 476 and the other between residues 74 and 122. The existence of two control points in different locations explains why the reduction in the experimental diffusion rate does not simply correlate with the width of the main gas channel. We also find that in the more effective mutation (V74M) CO molecules are still able to reach the active site through transitions that are gated by the microsecond dihedral motions of the side chain of R476 and the thermal fluctuations of the width of the gas channel defined by M74 and L122. Reflecting on the molecular information gained from simulation, we discuss future mutation experiments that could further lower the diffusion rates of small ligands inhibiting [NiFe]-hydrogenase.gas diffusion | mean first passage times T here is currently a strong research effort in developing biology-inspired approaches for the production of renewable energy sources. Examples include the use of natural or artificial photosystems for light harvesting and exciton generation (1, 2), hydrogenases for hydrogen production (3, 4) and oxidation in biofuel cells (5, 6), and carbon-monoxide dehydrogenase for CO 2 reduction and synthesis of precursors of biofuels (7, 8). Yet, a general problem associated with the use of biocatalysts is their sensitivity to changing environmental conditions. A good example is the inhibition of hydrogenases by diatomic molecules. Naturally evolved under anaerobic conditions, the enzyme becomes inhibited by molecular oxygen that is present in the atmosphere and only few species can resist oxidative damage. Thus, an important aspect of biotechnological approaches is the ability to design and engineer enzyme variants that are more robust and durable than their natural counterparts.In the field of hydrogenase research, three strategies have been proposed to reduce the effect of inhibition or damage (5): (i) restricting the access of gas molecules to the active site, (ii) lowering the binding affinity of the gas molecules to the metal centers, and (iii) facilitating the removal of undesired oxidation products. Recently, evidence was found that oxygen-tolerance in the membrane-bound [NiFe]-hydrogenase from the Knallgas bacterium Ralstonia eutropha...

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“…Historically, globins have served as a model system for understanding how ligand flux through heme protein scaffolds controls gas-binding properties. Over the past 50 y, studies on myoglobin have utilized X-ray crystallography (9), time-resolved absorption techniques (10), CO photolysis of protein crystals (11,12), and computational methods (13,14) to provide a detailed molecular picture of ligand migration through the globin fold. Experimental approaches have implicated a histidine residue, the "His(E7) gate" (15), as the primary route for ligand entry and exit, in contrast to computational studies that have identified multiple ligand migration pathways (14).…”

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confidence: 99%

Tunnels modulate ligand flux in a heme nitric oxide/oxygen binding (H-NOX) domain

Winter

Herzik

Kuriyan

et al. 2011

Proc. Natl. Acad. Sci. U.S.A.

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Interior topological features, such as pockets and channels, have evolved in proteins to regulate biological functions by facilitating the diffusion of biomolecules. Decades of research using the globins as model heme proteins have clearly highlighted the importance of gas pockets around the heme in controlling the capture and release of O 2 . However, much less is known about how ligand migration contributes to the diverse functions of other heme protein scaffolds. Heme nitric oxide/oxygen binding (H-NOX) domains are a conserved family of gas-sensing heme proteins with a divergent fold that are critical to numerous signaling pathways. Utilizing X-ray crystallography with xenon, a tunnel network has been shown to serve as a molecular pathway for ligand diffusion. Structure-guided mutagenesis results show that the tunnels have unexpected effects on gas-sensing properties in H-NOX domains. The findings provide insights on how the flux of biomolecules through protein scaffolds modulates protein chemistry.

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Ligand diffusion in globins: simulations versus experiment

Cited by 78 publications

References 56 publications

Hydrophobic Effect Drives Oxygen Uptake in Myoglobin via Histidine E7

Hydrophobic Effect Drives Oxygen Uptake in Myoglobin via Histidine E7

Mechanistic insight into the blocking of CO diffusion in [NiFe]-hydrogenase mutants through multiscale simulation

Tunnels modulate ligand flux in a heme nitric oxide/oxygen binding (H-NOX) domain

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