A thiocarbonate sink on the enzymatic energy landscape of aerobic CO oxidation? Answers from DFT and QM/MM models of Mo Cu CO-dehydrogenases

Rovaletti, Anna; Bruschi, Maurizio; Moro, Giorgio; Cosentino, Ugo; Ryde, Ulf; Greco, Claudio

doi:10.1016/j.jcat.2019.02.032

Cited by 13 publications

(15 citation statements)

References 39 publications

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“… is also rather large (11 kcal/mol), whereas all other intermediates exhibit a difference in relative energy that is less than 5 kcal/mol, i.e. similar to what is observed for other systems [ 26 ].…”

Section: Resultssupporting

confidence: 70%

“…In this paper, we have deepened our insights about the energetics of the putative initial steps for dihydrogen oxidation by MoCu CO dehydrogenase, keeping as a reference the QM/MM results from our previous investigation of the hydrogenase activity [ 13 ]. The energies were refined by using the BigQM approach on the QM/MM optimised geometries, analogously to our previous work on the CO-oxidation catalysis by this enzyme [ 26 ]. Unexpectedly, we observed large deviations in the relative energies obtained by the two approaches.…”

Section: Discussionmentioning

confidence: 99%

“…The latter is composed by all groups within 4.5–6 Å from the QM system of the QM/MM calculation, all buried charged groups in the protein and by moving truncated groups three residues away from the active site [ 23 ]. A previous QM/MM study of the first steps of the CO oxidation reaction in MoCu-CODH [ 26 ] indicated that BigQM-based refinement of computed energies is a valuable approach also in the theoretical investigation of the latter enzyme.…”

Section: Introductionmentioning

confidence: 99%

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QM/MM study of the binding of H2 to MoCu CO dehydrogenase: development and applications of improved H2 van der Waals parameters

2021

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The MoCu CO dehydrogenase enzyme not only transforms CO into CO2 but it can also oxidise H2. Even if its hydrogenase activity has been known for decades, a debate is ongoing on the most plausible mode for the binding of H2 to the enzyme active site and the hydrogen oxidation mechanism. In the present work, we provide a new perspective on the MoCu-CODH hydrogenase activity by improving the in silico description of the enzyme. Energy refinement—by means of the BigQM approach—was performed on the intermediates involved in the dihydrogen oxidation catalysis reported in our previously published work (Rovaletti, et al. “Theoretical Insights into the Aerobic Hydrogenase Activity of Molybdenum–Copper CO Dehydrogenase.” Inorganics 7 (2019) 135). A suboptimal description of the H2–HN(backbone) interaction was observed when the van der Waals parameters described in previous literature for H2 were employed. Therefore, a new set of van der Waals parameters is developed here in order to better describe the hydrogen–backbone interaction. They give rise to improved binding modes of H2 in the active site of MoCu CO dehydrogenase. Implications of the resulting outcomes for a better understanding of hydrogen oxidation catalysis mechanisms are proposed and discussed.

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Section: Resultssupporting

confidence: 70%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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QM/MM study of the binding of H2 to MoCu CO dehydrogenase: development and applications of improved H2 van der Waals parameters

2021

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“…Only the large subunit (CoxL) of one monomer, containing the active site, was considered in this study. The enzyme was set up in the same way as in our previous study [28]. The protonation state of all the residues was determined based on calculations with PROPKA [29] and on studies of the hydrogen-bond pattern, of the solvent accessibility and of the possible formation of ionic pairs.…”

Section: The Proteinmentioning

confidence: 99%

“…The protein was solvated with water molecules, forming a sphere with a radius of 60 Å around the geometric centre of the protein. The added protons and water molecules were then optimised by a 1-ns simulated-annealing molecular-dynamics simulation, followed by energy minimization [28] (for details on the adopted force field, see the next subsection).…”

Section: The Proteinmentioning

confidence: 99%

Theoretical Insights into the Aerobic Hydrogenase Activity of Molybdenum–Copper CO Dehydrogenase

et al. 2019

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The Mo/Cu-dependent CO dehydrogenase from O. carboxydovorans is an enzyme that is able to catalyse CO oxidation to CO 2 ; moreover, it also expresses hydrogenase activity, as it is able to oxidize H 2 . Here, we have studied the dihydrogen oxidation catalysis by this enzyme using QM/MM calculations. Our results indicate that the equatorial oxo ligand of Mo is the best suited base for catalysis. Moreover, extraction of the first proton from H 2 by means of this basic centre leads to the formation of a Mo–OH–Cu I H hydride that allows for the stabilization of the copper hydride, otherwise known to be very unstable. In light of our results, two mechanisms for the hydrogenase activity of the enzyme are proposed. The first reactive channel depends on protonation of the sulphur atom of a Cu-bound cysteine residues, which appears to favour the binding and activation of the substrate. The second reactive channel involves a frustrated Lewis pair, formed by the equatorial oxo group bound to Mo and by the copper centre. In this case, no binding of the hydrogen molecule to the Cu center is observed but once H 2 enters into the active site, it can be split following a low-energy path.

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[MoCu]‐Dependent Carbon Monoxide Dehydrogenases

Gillett,

Grinter,

Greening

2024

Encyclopedia of Inorganic and Bioinorganic Chemistry

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[MoCu]‐dependent carbon monoxide dehydrogenases (Mo‐CODH) catalyze the hydroxylation of CO, which produces CO 2 and consumes H 2 O in the process. Aerobic carbon monoxide oxidizing bacteria and archaea use Mo‐CODH to generate energy by providing the respiratory chain with CO‐derived electrons, and aerobic CO‐oxidizers that possess the genes for CO 2 fixation can also use CO as a carbon source. Due to the pervasive nature of CO in the atmosphere as a trace gas, and the numerous marine and terrestrial environments enriched in CO due to its production during the decomposition of organic matter, aerobic CO‐oxidizers are widespread and significantly contribute to the biogeochemical cycle of CO. Mo‐CODH has been structurally characterized by both X‐ray crystallography and cryo‐EM. Structural and biochemical characterization of the purified Mo‐CODH enzyme has focused on bacteria that mediate carboxydotrophic growth such as Afipia carboxidovorans , which were isolated from environments with elevated concentrations of CO. Only recently has a Mo‐CODH enzyme capable of oxidizing CO to subatmospheric levels been isolated and characterized, from Mycobacterium smegmatis, providing the first insights into structural features that enable high‐affinity CO oxidation. In all aerobic CO oxidizers, CO oxidation occurs at a unique [MoSCu] dimetallic site within the active site of Mo‐CODH, through a mechanism that has been the subject of several computational and biochemical studies. Two [2Fe–2S] clusters facilitate the transport of electrons from the active site to a FAD cofactor, which then donates electrons to an electron carrier. Quinones are believed to be the primary physiological electron acceptor of Mo‐CODH, which can be transported from the cell membrane through the cytoplasm to the soluble Mo‐CODH complex by the CoxG shuttle protein.

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A thiocarbonate sink on the enzymatic energy landscape of aerobic CO oxidation? Answers from DFT and QM/MM models of Mo Cu CO-dehydrogenases

Cited by 13 publications

References 39 publications

QM/MM study of the binding of H2 to MoCu CO dehydrogenase: development and applications of improved H2 van der Waals parameters

QM/MM study of the binding of H2 to MoCu CO dehydrogenase: development and applications of improved H2 van der Waals parameters

Theoretical Insights into the Aerobic Hydrogenase Activity of Molybdenum–Copper CO Dehydrogenase

[MoCu]‐Dependent Carbon Monoxide Dehydrogenases

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