ArticleProceedings of the National Academy of Sciences of the United States of America2012
Mechanistic insight into the blocking of CO diffusion in [NiFe]-hydrogenase mutants through multiscale simulation.
Article in Proceedings of the National Academy of Sciences of the United States of America, 2012. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 18 papers.
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18 citing papers in PubMed, 59 citations in OpenAlex.
- Symmetric Ligand Binding Pathways and Dual-State Bottleneck in [NiFe] Hydrogenases from Unbiased Molecular Dynamics.The journal of physical chemistry letters · 2025Article
- PathInHydro, a Set of Machine Learning Models to Identify Unbinding Pathways of Gas Molecules in [NiFe] Hydrogenases.Journal of chemical information and modeling · 2025Article
- Characterization of the Bottlenecks and Pathways for Inhibitor Dissociation from [NiFe] Hydrogenase.Journal of chemical information and modeling · 2024Article
- Microbial oxidation of atmospheric trace gases.Nature reviews. Microbiology · 2022Review
- Second and Outer Coordination Sphere Effects in Nitrogenase, Hydrogenase, Formate Dehydrogenase, and CO Dehydrogenase.Chemical reviews · 2022Review
- Charge Transport in Organic Semiconductors: The Perspective from Nonadiabatic Molecular Dynamics.Accounts of chemical research · 2022Review
- Small-Molecule Tunnels in Metalloenzymes Viewed as Extensions of the Active Site.Accounts of chemical research · 2021Review
- Gas Sensing by Bacterial H-NOX Proteins: An MD Study.Molecules (Basel, Switzerland) · 2020Article
- Ribonucleotide Reductase Requires Subunit Switching in Hypoxia to Maintain DNA Replication.Molecular cell · 2017Article
- Mechanism of ONature chemistry · 2017Article
- Control of the Position of Oxygen Delivery in Soybean Lipoxygenase-1 by Amino Acid Side Chains within a Gas Migration Channel.The Journal of biological chemistry · 2016Article
- Exploration of gated ligand binding recognizes an allosteric site for blocking FABP4-protein interaction.Physical chemistry chemical physics : PCCP · 2015Article
- Oxygen diffusion pathways in a cofactor-independent dioxygenase.Chemical science · 2015Article
- Identification of Mutational Hot Spots for Substrate Diffusion: Application to Myoglobin.Journal of chemical theory and computation · 2015Article
- Aerobic damage to [FeFe]-hydrogenases: activation barriers for the chemical attachment of O2.Angewandte Chemie (International ed. in English) · 2014Article
- Exploring the diffusion of molecular oxygen in the red fluorescent protein mCherry using explicit oxygen molecular dynamics simulations.The journal of physical chemistry. B · 2013Article
- A computational study of water and CO migration sites and channels inside myoglobin.Journal of chemical theory and computation · 2013Article
- Relation between anaerobic inactivation and oxygen tolerance in a large series of NiFe hydrogenase mutants.Proceedings of the National Academy of Sciences of the United States of America · 2012Article
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Authors and funding
2 authors at 1 institution in 1 country.
Funding
No grant is acknowledged in the PubMed record.
Abstract
[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.
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