Search

Molecular modeling techniques have become indispensable in many fields of molecular sciences in which the details related to mechanisms and reactivity need to be studied at an atomistic level. This review article provides a collection of computational modeling works on a topic of enormous interest and urgent relevance: the properties of metalloenzymes involved in the degradation and valorization of natural biopolymers and synthetic plastics on the basis of both circular biofuel production and bioremediation strategies. In particular, we will focus on lytic polysaccharide monooxygenase, laccases, and various heme peroxidases involved in the processing of polysaccharides, lignins, rubbers, and some synthetic polymers. Special attention will be dedicated to the interaction between these enzymes and their substrate studied at different levels of theory, starting from classical molecular docking and molecular dynamics techniques up to techniques based on quantum chemistry.

De novo metalloprotein design is a remarkable approach to shape protein scaffolds toward specific functions. Here, we report the design and characterization of Due Rame 1 (DR1), a de novo designed protein housing a di-copper site and mimicking the Type 3 (T3) copper-containing polyphenol oxidases (PPOs). To achieve this goal, we hierarchically designed the first and the second di-metal coordination spheres to engineer the di-copper site into a simple four-helix bundle scaffold. Spectroscopic, thermodynamic, and functional characterization revealed that DR1 recapitulates the T3 copper site, supporting different copper redox states, and being active in the O 2 -dependent oxidation of catechols to o -quinones. Careful design of the residues lining the substrate access site endows DR1 with substrate recognition, as revealed by Hammet analysis and computational studies on substituted catechols. This study represents a premier example in the construction of a functional T3 copper site into a designed four-helix bundle protein.

This perspective aims at illustrating a computational viewpoint on some specific issues concerning structure–activity relationships related to [FeFe]-hydrogenase ([FeFe]-H2ase) biomimicry. Most of the research outlined herein has been addressed by means of density functional theory (DFT) based tools, in some cases in conjunction with experimental techniques. The number of computational, experimental and mixed approach studies on the “hydrogenase models” topic is extraordinarily high. Accordingly, several comprehensive reviews have been published over the last twenty years. Moreover, the number of iron compounds of increasing nuclearity that have been considered as “biomimetic models” of [FeFe]-H2ase has grown exponentially over time. Additionally, the issues regarding some mismatches existing between the natural system and related synthetic analogues, are quite variegated. As a consequence of the countless examples that could be considered as related to “hydrogenase mimicry”, the intent of the present contribution is to provide an account of a limited number of recent study cases, in which DFT has been employed to elucidate redox properties, reactivity issues of selected examples of diiron biomimicry. Herein the treated topics have been explicitly chosen to show how DFT has allowed us to rationalize and complement experimental observations, with a special focus on electrocatalysis aspects. Finally, the specific purpose of this perspective is to show how mutually intertwined are the various issues concerning a fascinating branch of biomimetic research.

Hydrogenases are enzymes that catalyze the oxidation and production of molecular hydrogen. For about fifteen years, there have been many reports about the successful connection of these enzymes to photosensitizers with the aim of designing H2 photoproduction systems, but relatively little attention has been paid to whether and why illumination may affect the catalytic properties of the enzyme. In all hydrogenases, hydrogen activation occurs at an inorganic active site that includes at least one Fe-carbonyl motif, which may make it sensitive to irradiation. Here we review the evidence that hydrogenases are indeed photosensitive. We focus mainly on the so-called FeFe hydrogenases; their active site, called the H-cluster, consists of a [4Fe4S] cluster that is bound by a cysteine sulfur to a diiron site. The iron atoms of the binuclear cluster are coordinated by carbonyl and cyanide ligands and an azadithiolate group. We describe the effects of UV-visible light irradiation on the enzyme under cryogenic or turnover conditions and the photoreactivity of model complexes that mimic the diiron site. We emphasize the dependence of the photochemical processes on wavelength, and warn about FeFe hydrogenase photoinhibition, which should probably be considered when attempts are made to use FeFe hydrogenases for the artificial photosynthesis of solar fuels. We also underline the relevance of studies of synthetic mimics of the H-cluster for understanding at atomistic level the photochemical processes observed in the enzyme.

International audience; The synthesis, characterization, and protonation of [Fe2(CO)6{(μ-SCH2)2(Et)P═O}] (1) using the moderately strong acid CF3CO2H (pKaMeCN = 12.7) are reported. Digital simulations of the cyclic voltammetry of 1 in the presence of CF3CO2H and DFT calculations have allowed us to obtain a detailed mechanistic picture of the processes underlying the catalytic hydrogen evolution reaction (HER) that 1 can mediate. Moreover, DFT has shed light on the role of the P═O functionality in the whole catalytic cycle of proton reduction. The reductive behavior of 1 features a double electron transfer with potential inversion, which is associated with deep structural rearrangement of the catalyst. The double reduction appears also functional to the intramolecular proton transfer from the P═O group to the diiron core, a crucial process for the H+/H– heterocoupling yielding H2. The key intermediate for the H2 formation and release is predicted to be a 3H+/3e– species, in which P═O is perfectly poised to shuttle protons from solution to the Fe–H–Fe moiety. Therefore, the R-P═O bridgehead installed in a dithiolato linker of a diiron core proves a valid and versatile alternative to the natural nitrogen-based Fe2 strap.

FeIFeI Fe2(S2C3H6)(CO)6(µ-CO) (1a–CO) and its FeIFeII cationic species (2a+–CO) are the simplest model of the CO-inhibited [FeFe] hydrogenase active site, which is known to undergo CO photolysis within a temperature-dependent process whose products and mechanism are still a matter of debate. Using density functional theory (DFT) and time-dependent density functional theory (TDDFT) computations, the ground state and low-lying excited-state potential energy surfaces (PESs) of 1a–CO and 2a+–CO have been explored aimed at elucidating the dynamics of the CO photolysis yielding Fe2(S2C3H6)(CO)6 (1a) and [Fe2(S2C3H6)(CO)6]+ (2a+), two simple models of the catalytic site of the enzyme. Two main results came out from these investigations. First, a–CO and 2a+–CO are both bound with respect to any CO dissociation with the lowest free energy barriers around 10 kcal mol−1, suggesting that at least 2a+–CO may be synthesized. Second, focusing on the cationic form, we found at least two clear excited-state channels along the PESs of 2a+–CO that are unbound with respect to equatorial CO dissociation.

International audience; The so-called FeFe hydrogenases catalyze H2 production and oxidation at a dinuclear inorganic active site. Some of them can be natively purified in an overoxidized, O2-resistant “Hinact” state, recently identified by Rodríguez-Maciá et al. as the product of the reaction of the enzyme with sulfide [Rodríguez-Maciá, P.; J. Am. Chem. Soc. 2018, 140, 9346]. We used a combination of direct electrochemistry experiments with the FeFe hydrogenase from Chlamydomonas reinhardtii, site-directed mutagenesis, molecular dynamics and density functional theory (DFT) calculations to describe the mechanism of inhibition: the diffusion of the inhibitor in the enzyme and its subsequent reaction at the active site H-cluster. We conclude that hydrogen sulfide (H2S) inhibits the enzyme noncompetitively, in a first step by replacing a conserved water molecule that is involved in proton transfer, and then binding to the active site as a hydrosulfide ligand (HS–). DFT calculations with the PBE0-D3 functional successfully describe the redox state of the cubane fragment of the H-cluster in the resulting “Htrans” state. Our experimental and theoretical results are consistent with the reactivation involving the reduction of the H-cluster in the Htrans state, followed by the potentiometric or catalytic reoxidation of the enzyme. This mechanism reconciles all experimental observations, and we suggest that it is common to all FeFe hydrogenases. In addition, we observe that the hydrogenases from Megasphaera elsdenii, Clostridium acetobutylicum (CaI), and Clostridium pasteurianum (CpI) are also inhibited by sulfide, but with very slow kinetics. Although sulfide inhibition is fully reversible, we observed an irreversible inactivation by polysulfide contaminants, which should be avoided if the hydrogenase is exposed to sulfide to prepare samples that are protected from air, e.g., for transport or storage.*

Oxidative stress and metal dyshomeostasis are considered as crucial factors in the pathogenesis of Alzheimer's disease (AD). Indeed, transition metal ions such as Cu(ii) can generate Reactive Oxygen Species (ROS) via O2 Fenton-like reduction, catalyzed by Cu(ii) coordinated to the Amyloid beta (Aβ) peptide. Despite intensive effort, the mechanisms of ROS-induced molecular damage remain poorly understood. In the present paper, we investigate on the basis of molecular modelling computations the mechanism of OH radical propagation toward the Aβ peptide, starting from the end-product of OH radical generation by Cu(ii)·Aβ. We evaluate (i) the OH oxidative capacity, as well as the energetics of the possible Aβ oxidation target residues, by quantum chemistry Density Functional Theory (DFT) on coordination models of Cu(ii)/OH/Aβ and (ii) the motion of the OH˙ approaching the Aβ target residues by classical Molecular Dynamics (MD) on the full peptide Cu(ii)/OH/Aβ(1–16). The results show that the oxidative capacity of OH coordinated Cu(ii)Aβ is significantly lower than that of the free OH radical and that propagation toward Aβ Asp and His residues is favoured over Tyr residues. These results are discussed on the basis of the recent literature on in vitro Aβ metal-catalyzed oxidation and on the possible implications for the AD oxidative stress mechanism.

International audience; FeFe hydrogenases catalyse H2 oxidation and production using a "H-cluster", where two Fe ions are bound by an aza-dithiolate (adt) ligand. Various hypotheses have been proposed (by us and others) to explain that the enzyme reversibly inactivates under oxidizing, anaerobic conditions: intramolecular binding of the N atom of adt, formation of the so-called Hox/inact state or non-productive binding of H2 to isomers of the H-cluster. Here we show that none of the above explains the new finding that the anaerobic, oxidative, H2-dependent reversible inactivation is strictly dependent on the presence of Cl- or Br-. We provide experimental evidence that chloride uncompetitively inhibits the enzyme: it reversibly binds to catalytic intermediates of H2 oxidation (but not to the resting "Hox" state), after which oxidation locks the active site into a stable, saturated, inactive form, the structure of which is proposed here based on DFT calculations. The halides interact with the amine group of the H-cluster but do not directly bind to iron. It should be possible to stabilize the inhibited state in amounts compatible with spectroscopic investigations to explore further this unexpected reactivity of the H-cluster of hydrogenase.

Catalytic H2 oxidation has been dissected by means of DFT into the key steps common to the Fe2 unit of both the [FeFe]-hydrogenase cofactor and selected biomimics. The aim was to elucidate the molecular details underlying the very different performances of the two systems. We found that the better enzyme performance is based on a single iron atom that is maintained electron-poor, favoring H2 binding, although embedded within a highly electron-rich cofactor, ensuring a facile oxidation of the Fe2 -H2 adduct. This is due to 1) CN- coordinating to both iron atoms, due to their amphipathic Lewis acid/base properties, and 2) the 4Fe4S subunit further withdrawing electrons from the Fe2 core. Preserving a moderate electron deficiency at a single iron also helps the cofactor preserve hydride affinity, which favors H2 cleavage. Such valuable characteristics allow the biocatalyst to turnover close to equilibrium conditions. All previous biomimicry has shown, in contrast, the impossibility to properly balance the two apparently contrasting aforementioned requisites, although evident progress has been made by the H2 -ase community. Disclosure of the differences identified could inspire the design of novel biomimics, for instance, reconsidering the use of CN- in the catalyst architecture. Indeed, in the presence of bases normally employed in oxidative catalysis, undesired stable protonation at coordinated CN- , which affects the opposite process (proton reduction), could be overcome.

Lytic polysaccharide monooxygenases (LPMOs) are Cu-containing enzymes that facilitate the degradation of recalcitrant polysaccharides by the oxidative cleavage of glycosidic bonds. They are gaining rapidly increasing attention as key players in biomass conversion, especially for the production of second-generation biofuels. Elucidation of the detailed mechanism of the LPMO reaction is a major step toward the assessment and optimization of LPMO efficacy in industrial biotechnology, paving the way to utilization of sustainable fuel sources. Here, we used density functional theory calculations to study the reaction pathways suggested to date, exploiting a very large active-site model for a fungal AA9 LPMO and using a celloheptaose unit as a substrate mimic. We identify a copper oxyl intermediate as being responsible for H-atom abstraction from the substrate, followed by a rapid, water-assisted hydroxyl rebound, leading to substrate hydroxylation.

International audience; To learn from Nature how to create an efficient hydrogen-producing catalyst, much attention has been paid to the investigation of structural and functional biomimics of the active site of [FeFe]-hydrogenase. To understand their catalytic activities, the μ-S atoms of the dithiolate bridge have been considered as possible basic sites during the catalytic processes. For this reason, a series of [FeFe]-H2ase mimics have been synthesized and characterized. Different [FeFe]-hydrogenase model complexes containing bulky Si–heteroaromatic systems or fluorene directly attached to the dithiolate moiety as well as their mono-PPh3-substituted derivatives have been prepared and investigated in detail by spectroscopic, electrochemical, X-ray diffraction, and computational methods. The assembly of the herein reported series of complexes shows that the μ-S atoms can be a favored basic site in the catalytic process. Small changes in the (hetero)-aromatic system of the dithiolate moiety are responsible for large differences in their structures. This was elucidated in detail by DFT calculations, which were consistent with the experimental results.

International audience; FeFe hydrogenases catalyze H-2 oxidation and formation at an inorganic active site (the "H-cluster"), which consists of a [Fe-2(CO)(3)(CN)(2)(dithiomethylamine)] subcluster covalently attached to a Fe4S4 subcluster. This active site is photosensitive: visible light has been shown to induce the release of exogenous CO (a reversible inhibitor of the enzyme), shuffle the intrinsic CO ligands, and even destroy the H-cluster. These reactions must be understood because they may negatively impact the Use of hydrogenase for the photoproduction of H-2. Here, we explore in great detail the reactivity of the excited states of the H-duster under catalytic conditions by examining, both experimentally and using TDDFT calculations, the simplest photochemical reaction: the binding and release of exogenous CO. A simple dyad model can be used to predict which excitations are active. This could be used for probing other, aspects of the photoreactivity of the H-cluster.

It is successfully shown that photocatalytic proton reduction to dihydrogen in the presence of a sacrificial electron donor, such as trimethylamine (TEA) and ascorbate, can be driven by compact sensitizer–catalyst dyads, that is, dithiolate-bridged [FeFe] hydrogenase models tethered to organic sensitizers, such as fluorenes and silafluorenes (1 a–4 a). The sensitizer–catalyst dyads 1 a–4 a show remarkable and promising catalytic activities as well as enhanced stabilities during photocatalysis performed under UV-light irradiation. The photocatalysis was carried out both in non-aqueous and aqueous media. The latter experiments were performed by solubilizing the photocatalysts within micelles formed by either sodium dodecyl sulfate (SDS) or cetyltrimethylammonium bromide (CTAB). In this study a turnover number of 539 (7 h) is achieved under optimized conditions, which corresponds to an exceptionally high turnover frequency of 77 h−1. Theoretical investigations as well as emission decay experiments were performed to understand the observed phenomena together with the mechanisms of photocatalytic H2 generation.

Density functional theory has been used to study diiron dithiolates [HFe2(xdt)(PR3)n(CO)5-nX] (n = 0, 2, 4; R = H, Me, Et; X = CH3S-, PMe3, NHC = 1,3-dimethylimidazol-2-ylidene; xdt = adt, pdt; adt = azadithiolate; pdt = propanedithiolate). These species are related to the [FeFe]-hydrogenases catalyzing the 2H+ + 2e- 虠 H2 reaction. Our study is focused on the reduction step following protonation of the Fe2(SR)2 core. Fe(H)s detected in solution are terminal (t-H) and bridging (μ-H) hydrides. Although unstable versus μ-Hs, synthetic t-Hs feature milder reduction potentials than μ-Hs. Accordingly, attempts were previously made to hinder the isomerization of t-H to μ-H. Herein, we present another strategy: in place of preventing isomerization, μ-H could be made a stronger oxidant than t-H (E°μ-H > E°t-H). The nature and number of PR3 unusually affect ΔE°t-H-μ-H: 4PEt3 models feature a μ-H with a milder E° than t-H, whereas the 4PMe3 analogues behave oppositely. The correlation ΔE°t-H-μ-H 虠 stereoelectronic features arises from the steric strain induced by bulky Et groups in 4PEt3 derivatives. One-electron reduction alleviates intramolecular repulsions only in μ-H species, which is reflected in the loss of bridging coordination. Conversely, in t-H, the strain is retained because a bridging CO holds together the Fe2 core. That implies that E°μ-H > E°t-H in 4-PEt3 species but not in 4PMe3 analogues. Also determinant to observe E°μ-H > E°t-H is the presence of a Fe apical σ-donor because its replacement with a CO yields E°μ-H < E°t-H even in 4PEt3 species. Variants with neutral NHC and PMe3 in place of CH3S- still feature E°μ-H > E°t-H. Replacing pdt with (Hadt)+ lowers E° but yields E°μ-H < E°t-H, indicating that μ-H activation can occur to the detriment of the overpotential increase. In conclusion, our results indicate that the electron richness of the Fe2 core influences ΔE°t-H-μ-H, provided that (i) the R size of PR3 must be greater than that of Me and (ii) an electron donor must be bound to Fe apically.

The [FeFe] hydrogenase is a highly sophisticated enzyme for the synthesis of hydrogen via a biological route. The rotated state of the H-cluster in the [FeIFeI] form was found to be an indispensable criteria for an effective catalysis. Mimicking the specific rotated geometry of the [FeFe] hydrogenase active site is highly challenging as no protein stabilization is present in model compounds. In order to simulate the sterically demanding environment of the nature's active site, the sterically crowded meso-bis(benzylthio)diphenylsilane (2) was utilized as dithiolate linker in an [2Fe2S] model complex. The reaction of the obtained hexacarbonyl complex 3 with 1,2-bis(dimethylphosphino)ethane (dmpe) results three different products depending on the amount of dmpe used in this reaction: [{Fe2(CO)5{μ-(SCHPh)2SiPh2}}2(μ-dmpe)] (4), [Fe2(CO)5(κ2-dmpe){μ-(SCHPh)2SiPh2}] (5) and [Fe2(CO)5(μ-dmpe){μ-(SCHPh)2SiPh2}] (6). Interestingly, the molecular structure of compound 5 shows a [FeFe] subsite comprising a semi-rotated conformation, which was fully characterized as well as the other isomers 4 and 6 by elemental analysis, IR and NMR spectroscopy, X-ray diffraction analysis (XRD) and DFT calculations. The herein reported model complex is the first example so far reported for [FeIFeI] hydrogenase model complex showing a semi-rotated geometry without the need of stabilization via agostic interactions (Fe⋯H-C). This journal is

The di-iron complex Fe-2(S2C3H6)(CO)(6) (a), one of the simplest functional models of the Fe-hydrogenases active site, is able to electrocatalyze proton reduction. In the present study, the H-2 evolving path catalyzed by a has been characterized using density functional theory. It is showed that, in the early stages of the catalytic cycle, a neutral mu-H adduct is formed; monoelectron reduction and subsequent protonation can give rise to a diprotonated neutral species (a-mu H-SH), which is characterized by a mu-H group, a protonated sulfur atom, and a CO group bridging the two iron centers, in agreement with experimental IR data indicating the formation of a long-lived mu-CO species. H-2 release from a-mu H-SH, and its less stable isomer a-H-2 is kinetically unfavorable, while the corresponding monoanionic compounds (a-mu H-SH- and a-H-2(-)) are more reactive in terms of dihydrogen evolution, in agreement with experimental data. The key species involved in electrocatalysis have structural features different from the hypothetical intermediates recently proposed to be involved in the enzymatic process, an observation that is possibly correlated with the reduced catalytic efficiency of the biomimetic di-iron assembly.

The experimental electron density of the high-performance thermoelectric material Zn4Sb3 has been determined by maximum entropy (MEM) analysis of short-wavelength synchrotron powder diffraction data. These data are found to be more accurate than conventional single-crystal data due to the reduction of common systematic errors, such as absorption, extinction and anomalous scattering. Analysis of the MEM electron density directly reveals interstitial Zn atoms and a partially occupied main Zn site. Two types of Sb atoms are observed: a free spherical ion (Sb3-) and Sb2(4-) dimers. Analysis of the MEM electron density also reveals possible Sb disorder along the c axis. The disorder, defects and vacancies are all features that contribute to the drastic reduction of the thermal conductivity of the material. Topological analysis of the thermally smeared MEM density has been carried out. Starting with the X-ray structure ab initio computational methods have been used to deconvolute structural information from the space-time data averaging inherent to the XRD experiment. The analysis reveals how interstitial Zn atoms and vacancies affect the electronic structure and transport properties of beta-Zn4Sb3. The structure consists of an ideal A12Sb10 framework in which point defects are distributed. We propose that the material is a 0.184:0.420:0.396 mixture of A12Sb10, A11BCSb10 and A10BCDSb10 cells, in which A, B, C and D are the four Zn sites in the X-ray structure. Given the similar density of states (DOS) of the A12Sb10, A11BCSb10 and A10BCDSb10 cells, one may electronically model the defective stoichiometry of the real system either by n-doping the 12-Zn atom cell or by p-doping the two 13-Zn atom cells. This leads to similar calculated Seebeck coefficients for the A12Sb10, A11BCSb10 and A10BCDSb10 cells (115.0, 123.0 and 110.3 microV K(-1) at T=670 K). The model system is therefore a p-doped semiconductor as found experimentally. The effect is dramatic if these cells are doped differently with respect to the experimental electron count. Thus, 0.33 extra electrons supplied to either kind of cell would increase the Seebeck coefficient to about 260 microV K(-1). Additional electrons would also lower sigma, so the resulting effect on the thermoelectric figure of merit of Zn4Sb3 challenges further experimental work.

Bromoperoxidase catalytic activity exerted by oxidated amavadin [V(HIDPA)2](-) (HIDPA = 2,2'-(hydroxyimino) dipropionate) in mono- and bis-protonated forms has been investigated by DFT. Possible reaction pathways for formation of peroxido/hydroperoxido complexes and subsequent bromide oxidation have been systematically dissected. The effect of increasing [H(+)] on catalytically active species and on halogenide oxidation has been also studied. Similarly to vanadium haloperoxidase (VHPO), the results point to a hydroperoxido amavadin adduct as the most reactive species toward bromide oxidation. However, comparison of the reactivity of amavadin and VHPO reveals also crucial differences in the catalytic mechanism of such natural V complexes.

Density functional theory (DFT) and time-dependent DFT (TDDFT) have been used to investigate how visible light photons can excite an asymmetrically substituted diiron hydride, [Fe2(pdt)(μ-H)(CO)4dppv] + (1+, dppv = cis-1,2-C2H2(PPh 2)2; pdt = 1,3-propanedithiolate), as well as the symmetric species [Fe2(pdt)(μ-H)(CO)4(PMe 3)2]+ (2+), which are the first photocatalysts of proton reduction operating without employing sensitizers (Wang, W.; Rauchfuss, T. B.; Bertini, L.; Zampella, G.; J. Am. Chem. Soc., 2012, 134, 4525). Theoretical results illustrate that the peculiar reactivity associated to the excited states of 1+ and 2+ is compatible with three different scenarios: (i) it can arise from the movement of the hydride ligand from fully bridging to semibridging/terminal coordination, which is expected to be more reactive toward protons; (ii) reactivity could be related to cleavage of a Fe-S bond, which implies formation of a transient Fe penta-coordinate species that would trigger a facile turnstile hydride isomerization, if lifetime excitation is long enough; (iii) also in line with a Fe-S bond cleavage is the possibility that after excited state decay, a highly basic S center is protonated so that a species simultaneously containing S-Hδ+ and Fe-Hδ- moieties is formed and, once reduced by a suitable electron donor, it can readily afford H2 plus an unprotonated form of the FeFe complex. This last possibility is consistent with 31P NMR and IR solution data. All the three possibilities are compatible with the capability of 1+ and 2+ to perform photocatalysis of hydrogen evolving reaction (HER) without sensitizer. Moreover, even though it turned out difficult to discriminate among the three scenarios, especially because of the lack of experimental excitation lifetimes, it is worth underscoring that all of the three pathways represent a novelty regarding diiron carbonyl photoreactivity, which is usually associated with CO loss. Results provide also a rationale to the experimental observations which showed that the simultaneous presence of donor ligands (dppv in the case of 1 +) and a H ligand in the coordination environment of diiron complexes is a key factor to prevent CO photodissociation and catalyze HER. Finally, the comparison of photoexcitation behavior of 1+ and 2+ allows a sort of generalization about the functioning of such hydride species. © 2013 American Chemical Society.

Amavadin is an unusual octa-coordinated V(IV) complex isolated from Amanita muscaria mushrooms. The outer-sphere catalytic properties of such a complex toward several oxidation reactions are well known. Nevertheless, a remarkable example exists, in which the V(V) (d(0)) oxidized form of amavadin is able to electro-catalyze the oxidation of some thiols to the corresponding disulfides through an inner-sphere mechanism (Guedes da Silva et al. J. Am. Chem. Soc.1996, 118, 7568-7573.) The reaction mechanism implies the formation of an amavadin-substrate intermediate, whose half-life is about 0.3 s. By means of Density Functional Theory (DFT) computations and Quantum Theory of Atoms in Molecules (QTAIM) analysis of the electron density, we have first characterized the stereoelectronic features of the V(IV) (inactive) and V(V) (active) states of amavadin. Then, the formation of the V(V) complex with methyl mercaptoacetate (MMA), which has been chosen as a prototypical substrate, has been characterized both thermodynamically and kinetically. DFT results reveal that protonation of V(V) amavadin at a carboxylate oxygen not directly involved in the V coordination, favors MMA binding into the first coordination sphere of vanadium, by substitution of the amavadin carboxylate oxygen with that of the substrate and formation of an S-HO hydrogen bond interaction. The latter interaction can promote SH deprotonation and binding of the thiolate group to vanadium. The kinetic and thermodynamic feasibility of the V(V)-MMA intermediates formation is in agreement, along with electrochemical experimental data, also with the biological role exerted by amavadin. Finally, the presence of an ester functional group as an essential requisite for MMA oxidation has been rationalized.

International audience; Carbon monoxide is often described as a competitive inhibitor of FeFe hydrogenases, and it is used for probing H-2 binding to synthetic or in silico models of the active site H-cluster. Yet it does not always behave as a simple inhibitor. Using an original approach which combines accurate electrochemical measurements and theoretical calculations, we elucidate the mechanism by which, under certain conditions, CO binding can cause permanent damage to the H-cluster. Like in the case of oxygen inhibition, the reaction with CO engages the entire H-cluster, rather than only the Fe-2 subsite.

[FeFe]-hydrogenases are highly efficient H(2)-evolving metalloenzymes that include cyanides and carbonyls in the active site. The latter is an Fe(6)S(6) cluster (the so-called H-cluster) that can be subdivided into a binuclear portion carrying the CO and CN(-) groups and a tetranuclear subcluster. The fundamental role of cyanide ligands in increasing the basicity of the H-cluster has been highlighted previously. Here a more subtle but crucial role played by the two CN(-) ligands in the active site of [FeFe]-hydrogenases is disclosed. In fact, QM/MM calculations on all-atom models of the enzyme from Desulfovibrio desulfuricans show that the cyanide groups fine-tune the electronic and redox properties of the active site, affecting both the protonation regiochemistry and electron transfer between the two subclusters of the H-cluster. Despite the crucial role of cyanides in the protein active site, the currently available bioinspired electrocatalysts generally lack CN(-) groups in order to avoid competition between the latter and the catalytic metal centers for proton binding. In this respect, we show that a targeted inclusion of phosphine ligands in hexanuclear biomimetic clusters may restore the electronic and redox features of the wild-type H-cluster.

Periodic density functional calculations using pseudopotentials and a local basis set were performed on the type I clathrates A(8)Ga(16)Ge(30) (A=Sr, Ba). Both are known to show promising thermoelectric properties. Ab initio wave functions were analyzed within the framework of the quantum theory of atoms in molecules. This enabled us to analyze both the charge transfer and bonding properties of the clathrate from a rigorous quantum mechanical viewpoint. The Ba and Sr centers were found to be largely ionic (charge: ca. +1.7 e) both in the smaller 20-atom and in the larger 24-atom cages, consistent with a Zintl-phase view of these type I clathrates. The assertion that the Sr atoms in the different cages have similar oxidation states is shown to be consistent with multiwavelength diffraction experiments on Sr(8)Ga(16)Ge(30); while the assertion of ionicity of the Sr center is supported by the observation that the adsorption edge lies close to that previously found in the Sr K-edge XANES spectra of Sr(OH)(2).8 H(2)O. As such, this work contradicts previous experimental and theoretical studies that claim that the guest atoms are neutral. We show that the discrepancy is related to the definitions used for electron transfer. Definitions based on electron displacement (rearrangement) in space, as in previous works, do not account for the variation in shape and volume of the atomic catchment regions upon change in the number and average locations of the particles in the system. Eventually, such definitions lead to underestimation of charge transfer. The large binding energy found in earlier work for Ba and Sr in these materials is found to be consistent with a simple picture of charge transfer from the guest to the frame. Preliminary investigations on a clathrate of perfect stoichiometry appear to rule out any important relationship between the observed increase in the thermoelectric figure of merit with increasing external pressure and host-guest charge transfer.