Understanding the tethered unhooking and rehooking of S2B in the reaction domain of FeMo-co, the active site of nitrogenase

Dance, Ian G.

doi:10.1039/d2dt02571j

Cited by 10 publications

(12 citation statements)

References 66 publications

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“…This isomer is predicted to be relatively high in energy (11.7 kcal/ mol using the QM-VI region) compared to E 2 -SH − @Fe6, likely due to steric repulsion involving the terminal SH − group and His195. This makes it an unlikely candidate for the E 2 state (previous results 12,30,35,40 also found a similar trend); however, as the results for E 0 and E 1 have revealed, stronger binding is found to Fe6 than Fe2, making N 2 binding to such a geometry with an open coordination site to Fe6 of interest.…”

Section: Nmentioning

confidence: 68%

“…15 A QM/MM study (using the TPSSh functional) from our research group in contrast suggested E 4 models with two bridging hydrides located on the same pair (SP) of Fe ions (Fe2 and Fe6) and with open belt sulfur bridges (terminal sulfhydryl groups) that were found to be energetically more favorable than models with closed belt sulfur bridges (including E 4 -DP-Fe2/6(5)). Such opening of protonated belt sulfides has also been discussed in computational work by Dance, 40 Raugei, 13 and recently by Ryde and co-workers. 35 Kinetic and spectroscopic studies 7,37,41−44 indicate that dinitrogen will bind to the E 4 state, while no binding has been directly observed in earlier E n states (with the role of E 3 unclear).…”

Section: Introductionmentioning

confidence: 70%

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Understanding the Electronic Structure Basis for N₂ Binding to FeMoco: A Systematic Quantum Mechanics/Molecular Mechanics Investigation

Pang

Björnsson

2023

Inorg. Chem.

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The FeMo cofactor (FeMoco) of Mo nitrogenase is responsible for reducing dinitrogen to ammonia, but it requires the addition of 3–4 e–/H+ pairs before N2 even binds. A binding site at the Fe2/Fe3/Fe6/Fe7 face of the cofactor has long been suggested based on mutation studies, with Fe2 or Fe6 nowadays being primarily discussed as possibilities. However, the nature of N2 binding to the cofactor is enigmatic as the metal ions are coordinatively saturated in the resting state with no obvious binding site. Furthermore, the cofactor consists of high-spin Fe(II)/Fe(III) ions (antiferromagnetically coupled but also mixed-valence delocalized), which are not known to bind N2. This suggests that an Fe binding site with a different molecular and electronic structure than the resting state must be responsible for the experimentally known N2 binding in the E4 state of FeMoco. We have systematically studied N2 binding to Fe2 and Fe6 sites of FeMoco at the broken-symmetry QM/MM level as a function of the redox-, spin-, and protonation state of the cofactor. The local and global electronic structure changes to the cofactor taking place during redox events, protonation, Fe–S cleavage, hydride formation, and N2 coordination are systematically analyzed. Localized orbital and quasi-restricted orbital analysis via diamagnetic substitution is used to get insights into the local single Fe ion electronic structure in various states of FeMoco. A few factors emerge as essential to N2 binding in the calculations: spin-pairing of dxz and dyz orbitals of the N2-binding Fe ion, a coordination change at the N2-binding Fe ion aided by a hemilabile protonated sulfur, and finally hydride ligation. The results show that N2 binding to E0 , E1 , and E2 models is generally unfavorable, likely due to the high-energy cost of stabilizing the necessary spin-paired electronic structure of the N2-binding Fe ion in a ligand environment that clearly favors high-spin states. The results for models of E4 , however, suggest a feasible model for why N2 binding occurs experimentally in the E4 state. E4 models with two bridging hydrides between Fe2 and Fe6 show much more favorable N2 binding than other models. When two hydrides coordinate to the same Fe ion, an increased ligand-field splitting due to octahedral coordination at either Fe2 or Fe6 is found. This altered ligand field makes it easier for the Fe ion to acquire a spin-paired electronic structure with doubly occupied dxz and dyz orbitals that backbond to a terminal N2 ligand. Within this model for N2 binding, both Fe2 and Fe6 emerge as possible binding site scenarios. Due to steric effects involving the His195 residue, affecting both the N2 ligand and the terminal SH– group, distinguishing between Fe2 and Fe6 is difficult; furthermore, the binding depends on the protonation state of His195.

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Section: Nmentioning

confidence: 68%

Section: Introductionmentioning

confidence: 70%

Understanding the Electronic Structure Basis for N₂ Binding to FeMoco: A Systematic Quantum Mechanics/Molecular Mechanics Investigation

Pang

Björnsson

2023

Inorg. Chem.

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“…These variables are shown on Chart 1. Not all combinations are possible: exo -Fe6–H impedes unhooking of S2B from Fe2, 39 and an intact Fe2–S2B–Fe6 bridge together with an Fe2–H–Fe6 bridge leaves no space for the binding of reducible N 2 . An H atom on S2B is included in all calculated structures due to its better calculated energy.…”

Section: Resultsmentioning

confidence: 99%

“…31–38 I have analysed the factors that influence this unhooking, and described the unhooking of S2B (or S2BH) from Fe2, tethered to Fe6, and the rehooking reaction. 39 2H + + 2e − → H 2 N 2 + 6H + + 6e − → 2NH 3 D 2 + 2H + + 2e − → 2HD…”

Section: Introductionmentioning

confidence: 99%

The binding of reducible N₂ in the reaction domain of nitrogenase

Dance

2023

Dalton Trans.

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“…Concurrently with this bridge formation, S2BH unhooks its bond to Fe2 and eventually is more than 3.2 Å from Fe2. Unhooking of S2B from Fe2 is a general property of ligated FeMo‐co, and the factors that influence it have been expounded, and the potential energy surfaces for interconversions of hooked and unhooked isomers described [21e] . In general the energy differences between hooked and unhooked isomers are <10 kcal mol −1 , and kinetic barriers for interconversions are up to 13 kcal mol −1 .…”

Section: Resultsmentioning

confidence: 99%

The HD Reaction of Nitrogenase: a Detailed Mechanism

Dance

2022

Chemistry A European J

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Nitrogenase is the enzyme that converts N2 to NH3 under ambient conditions. The chemical mechanism of this catalysis at the active site FeMo‐co [Fe7S9CMo(homocitrate)] is unknown. An obligatory co‐product is H2, while exogenous H2 is a competitive inhibitor. Isotopic substitution using exogenous D2 revealed the N2‐dependent reaction D2+2H++2e−→2HD (the ‘HD reaction’), together with a collection of additional experimental characteristics and requirements. This paper describes a detailed mechanism for the HD reaction, developed and elaborated using density functional simulations with a 486‐atom model of the active site and surrounding protein. First D2 binds at one Fe atom (endo‐Fe6 coordination position), where it is flanked by H−Fe6 (exo position) and H−Fe2 (endo position). Then there is synchronous transfer of these two H atoms to bound D2, forming one HD bound to Fe2 and a second HD bound to Fe6. These two HD dissociate sequentially. The final phase is recovery of the two flanking H atoms. These H atoms are generated, sequentially, by translocation of a proton from the protein surface to S3B of FeMo‐co and combination with introduced electrons. The first H atom migrates from S3B to exo‐Fe6 and the second from S3B to endo‐Fe2. Reaction energies and kinetic barriers are reported for all steps. This mechanism accounts for the experimental data: (a) stoichiometry; (b) the N2‐dependence results from promotional N2 bound at exo‐Fe2; (c) different N2 binding Km for the HD reaction and the NH3 formation reaction results from involvement of two different sites; (d) inhibition by CO; (e) the non‐occurrence of 2HD→H2+D2 results from the synchronicity of the two transfers of H to D2; (f) inhibition of HD production at high pN2 is by competitive binding of N2 at endo‐Fe6; (g) the non‐leakage of D to solvent follows from the hydrophobic environment and irreversibility of proton introduction.

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Understanding the tethered unhooking and rehooking of S2B in the reaction domain of FeMo-co, the active site of nitrogenase

Abstract: Energetically accessible reversible unhooking of S2B or S2BH from Fe2, as an intrinsic property of FeMo-co, needs to be considered in the formulation of mechanisms for the reactions of nitrogenase.

Cited by 10 publications

References 66 publications

Understanding the Electronic Structure Basis for N₂ Binding to FeMoco: A Systematic Quantum Mechanics/Molecular Mechanics Investigation

Understanding the Electronic Structure Basis for N₂ Binding to FeMoco: A Systematic Quantum Mechanics/Molecular Mechanics Investigation

The binding of reducible N₂ in the reaction domain of nitrogenase

The HD Reaction of Nitrogenase: a Detailed Mechanism

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Understanding the tethered unhooking and rehooking of S2B in the reaction domain of FeMo-co, the active site of nitrogenase

Abstract: Energetically accessible reversible unhooking of S2B or S2BH from Fe2, as an intrinsic property of FeMo-co, needs to be considered in the formulation of mechanisms for the reactions of nitrogenase.

Cited by 10 publications

References 66 publications

Understanding the Electronic Structure Basis for N2 Binding to FeMoco: A Systematic Quantum Mechanics/Molecular Mechanics Investigation

Understanding the Electronic Structure Basis for N2 Binding to FeMoco: A Systematic Quantum Mechanics/Molecular Mechanics Investigation

The binding of reducible N2 in the reaction domain of nitrogenase

The HD Reaction of Nitrogenase: a Detailed Mechanism

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Product

Resources

About

Understanding the Electronic Structure Basis for N₂ Binding to FeMoco: A Systematic Quantum Mechanics/Molecular Mechanics Investigation

Understanding the Electronic Structure Basis for N₂ Binding to FeMoco: A Systematic Quantum Mechanics/Molecular Mechanics Investigation

The binding of reducible N₂ in the reaction domain of nitrogenase