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A large number of catalysts for hydrogen evolution reaction (HER) that are related (structurally and/or functionally) to the active site of [FeFe]-hydrogenases (H-cluster) has been proposed in the past few decades. Very recently, a novel recipe for HER catalysts has been added to the list. This consists in the combination of a diiron core, a ligand that can act as an intramolecular weak base to support protonation (both features that are common to the H-cluster), and a peculiar carbyne ligand that bridges the two metal centers. For instance, complex [Fe2{μ-CNMe2}(μ-CO)(CO)(CN)Cp2] (4) proved to be catalytically active towards HER. The novelty related to this family of biomimicry is not only structural, but also mechanistic. Indeed, an unprecedented (in the context of hydrogenase mimicry) ligand-based mechanism of HER, which avoids protonation at metal, has been dissected by DFT. In order to increase catalytic activity of this “non dithiolate based” system, a systematic search of ligand modification is therefore desirable. In this regard, herein we present results of replacing CN− (the proton shuttle in 4) by other ligands such as CNCH2Ph (5), PPh3 (6) or azide (7). The redox behavior of these compounds has been tested, in the absence and presence of a proton source. CV experiments combined with DFT calculations have revealed and rationalized critical points entailed by modifications of stereo-electronic features of 4. However, understanding the key factors underlying the absence of catalytic activity of these new compounds can be beneficial for the design of future improved biomimicry related to HER. As an example, properly tailored hydrocarbyl complexes replacing dithiolates at the Fe2 core might allow recovering the fruitful electronic properties of cyanides, when coordinated to metal centers.

This work originated from the need to functionalize surfactant-coated inorganic nanoparticles for biomedical applications, a process that is limited by excess unbound surfactant. These limitations are connected to the bioconjugation of targeting molecules that are often in equilibrium between the free aliquot in solution and that which binds the surface of the nanoparticles. The excess in solution can play a role in the biocompatability in vitro and in vivo of the final nanoparticles stock. For this purpose, we tested the ability of common surfactants - monothiolated polyethylene glycol and amphiphilic polymers - to colloidally stabilize nanoparticles as excess surfactant is removed and compared them to newly appearing multidentate surfactants endowed with high avidity for inorganic nanoparticles. Our results showed that monothiolated polyethylene glycol or amphiphilic polymers have an insufficient affinity to the nanoparticles and as the excess surfactant is removed the colloidal stability is lost, while multidentate high-avidity surfactants excel in the same regard, possibly allowing improvement in an array of nanoparticle applications, especially in those stated.

In endemic regions (West Africa and the Congo Basin), the genetic diversity of monkeypox virus (MPXV) is geographically structured into two major clades (clade I and II) that differ in virulence and host associations. Clade IIb is closely related to the B.1 lineage, which is dominating a worldwide outbreak initiated in 2022. Lineage B.1 has however accumulated mutations of unknown significance that most likely result from APOBEC3 (apolipoprotein B mRNA editing catalytic polypeptide-like 3) editing. We applied a population genetics-phylogenetics approach to investigate the evolution of MPXV during historical viral spread in Africa and to infer the distribution of fitness effects. We observed a high preponderance of codons evolving under strong purifying selection, particularly in viral genes involved in morphogenesis and replication or transcription. However, signals of positive selection were also detected and were enriched in genes involved in immunomodulation and/or virulence. In particular, several genes showing evidence of positive selection were found to hijack different steps of the cellular pathway that senses cytosolic DNA. Also, a few selected sites in genes that are not directly involved in immunomodulation are suggestive of antibody escape or other immuno-mediated pressures. Because orthopoxvirus host range is primarily determined by the interaction with the host immune system, we suggest that the positive selection signals represent signatures of host adaptation and contribute to the different virulence of clade I and II MPXV. We also used the calculated selection coefficients to infer the effects of mutations that define the predominant hMPXV1 lineage B.1, as well as the changes that have been accumulating during the worldwide outbreak. Results indicated that a proportion of deleterious mutations were purged from the predominant outbreak lineage, whose spread was not driven by the presence of beneficial changes. Polymorphic mutations with a predicted beneficial effect on fitness are few and have a low frequency. It remains to be determined whether they have any significance for ongoing virus evolution.

Three hexacarbonyl diiron dithiolate complexes [Fe2(CO)6(μ-(SCH2)2X)] with different substituted bridgeheads (X=CH2, CEt2, CBn2 (Bn=CH2C6H5)), have been studied under the same experimental conditions by cyclic voltammetry in dichloromethane [NBu4][PF6] 0.2 M. DFT calculations were performed to rationalize the mechanism of reduction of these compounds. The three complexes undergo a two-electron transfer whose the mechanism depends on the bulkiness of the dithiolate bridge, which involves a different timing of the structural changes (Fe−S bond cleavage, inversion of conformation and CO bridging) vs redox steps. The introduction of a bulky group in the dithiolate linker has obviously an effect on normally ordered (as for propanedithiolate (pdt)) or inverted (pdtEt2, pdtBn2) reduction potentials. Et→Bn replacement is not theoretically predicted to alter the geometry and energy of the most stable mono-reduced and bi-reduced forms but such a replacement alters the kinetics of the electron transfer vs the structural changes.

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.

Oxidative stress and metal dyshomeostasis are considered 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 efforts, the mechanisms of ROS-induced molecular damage remain poorly understood. In the present paper, we investigate, on the basis of Density Functional Theory (DFT) computations, a possible mechanism of the OH radical propagation toward membrane phospholipid polar head and fatty acid chains starting from the end-product of the OH radical generation by Cu(II)-Aβ. Using phosphatidylcholine as a model of a single unit inside a membrane, we evaluated the thermochemistry of the OH propagation with the oxidation of a C-H bond and the formation of the radical moiety. The DFT results show that Cu(II)-Aβ-OH can oxidize only sn-2 C-H bonds of the polar head and can easily oxidize the C-H bond adjacent to the carbon–carbon double bond in a mono or bis unsaturated fatty acid chain. These results are discussed on the basis of the recent literature on in vitro Aβ metal-catalyzed oxidation and on the possible implications in the AD oxidative stress mechanism.

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.

Nitrogen gas is a highly inert molecule and its activation under mild conditions represents a crucial goal in current research. In a recent study, the discovery of low-valence Ca(i) compounds capable of coordinating and reducing N2 was reported [B. Rösch, T. X. Gentner, J. Langer, C. Färber, J. Eyselein, L. Zhao, C. Ding, G. Frenking and S. Harder, Science, 2021, 371, 1125]. The study of low-valence alkaline earth complexes represents a new horizon in inorganic chemistry and demonstrates examples of spectacular reactivity. For example, complexes of the [BDI]2Mg2 type are selective reducing reagents in both organic and inorganic synthesis reactions. To date, however, no activity of Mg(i) complexes in the activation of the nitrogen molecule has been reported. By computational studies, in the present work, we investigated the analogies and differences of low-valence Ca(i) and Mg(i) complexes in the coordination, activation and protonation of N2. We have shown that the possibility of alkaline earth metals to employ atomic orbitals of the d type is reflected in the differences in the N2 binding energy and its coordination mode (end-on vs. side-on), as well as in the spin state of the resulting adduct (singlet vs. triplet). These divergences are finally observed in the subsequent protonation reaction, which turned out to be prohibitive in the presence of Mg.

One of the more active areas in bioorganometallic chemistry is the preparation and reactivity studies of active site mimics of the [NiFe]-hydrogenases. One area of particular recent progress involves reactions that interconvert Ni(μ-X)Fe centers for X = OH, H, CO, as described by Song et al. Such reactions illustrate new ways to access intermediates related to the Ni-R and Ni-SI states of the enzyme. Most models are derivatives of the type (diphosphine)Ni(SR)2Fe(CO)3-n(PR′3)n. In recent work, the methodology has been generalized to include FeII(diphosphine) derivatives of Ni(N2S2), where N2S22- is the tetradentate diamine-dithiolate (CH2N(CH3)CH2CH2S-)2. Indeed, models based on Ni(N2S2) have proven valuable, but these studies also highlight challenges in working with heterobimetallic complexes, specifically the tendency of some such Ni-Fe complexes to convert to homometalliic Ni-Ni derivatives. This kind of problem is not readily detected by X-ray crystallography. With this caution in mind, we argue that one series of complexes recently described in this journal are almost certainly misassigned.

Oxidative stress and copper dyshomeostasis are well established factors in the course of Alzheimer's disease (AD). Indeed, the pathological interaction of copper with the amyloid peptide is able to induce reactive oxygen species (ROS) production through a three-step cycle in which O2 is gradually reduced to superoxide, oxygen peroxide and finally to highly neurotoxic OH⋅ radicals. The purpose of this study has been to investigate at a computational level, by Density Functional Theory (DFT) and molecular mechanics techniques, the final two steps of O2 reduction to OH− +OH radical i.e the superoxide and hydroperoxide reduction by ascorbate, on different Cu(II) ⋅ Aβ coordination models. At variance with the first step of O2 reduction to O2.− characterized by high energy barrier, the successive O2.− and O2H− reductions are low energy barriers processes and that the OH⋅ radical formation is further favored by the possibility of Cu(II) ⋅ Aβ to form the Asp1 amino terminal radical. We discuss the results obtained from the perspective of the recent findings in the Aβ redox chemistry in AD pathology.

Density functional theory (DFT) calculations on Fe(2)S(2)(CO)(6−2n)(PMe(3))(2n) for n = 0, 1, and 2 reveal that the most electron-rich derivatives (n = 2) exist as diferrous disulfides lacking an S–S bond. The thermal interconversion of the Fe(II)(2)(S)(2) and Fe(I)(2)(S(2)) valence isomers is symmetry-forbidden. Related electron-rich diiron complexes [Fe(2)S(2)(CN)(2)(CO)(4)](2−) of an uncertain structure are implicated in the biosynthesis of [FeFe]-hydrogenases. Several efforts to synthesize electron-rich derivatives of Fe(2)(μ-S(2))(CO)(6) (1) are described. First, salts of iron persulfido cyanides [Fe(2)(μ-S(2))(CO)(5)(CN)](−) and [Fe(2)(μ-S(2))(CN)(CO)(4)(PPh(3))](−) were prepared by the reactions of NaN(tms)(2) with 1 and Fe(2)(μ-S(2))(CO)(5)(PPh(3)), respectively. Alternative approaches to electron-rich diiron disulfides targeted Fe(2)(μ-S(2))(CO)(4)(diphosphine). Whereas the preparation of Fe(2)(μ-S(2))(CO)(4)(dppbz) was straightforward, that of Fe(2)(μ-S(2))(CO)(4)(dppv) required an indirect route involving the oxidation of Fe(2)(μ-SH)(2)(CO)(4)(dppv) (dppbz = C(6)H(4)-1,2-(PPh(2))(2), dppv = cis-C(2)H(2)(PPh(2))(2)). DFT calculations indicate that the oxidation of Fe(2)(μ-SH)(2)(CO)(4)(dppv) produces singlet diferrous disulfide Fe(2)(μ-S)(2)(CO)(4)(dppv), which is sufficiently long-lived as to be trapped by ethylene. The reaction of 1 and dppv mainly afforded Fe(2)(μ-SCH=CHPPh(2))(μ-SPPh(2))(CO)(5), implicating a S-centered reaction.

International audience; A series of triiron clusters [Fe3(CO)5(2-dppe)(µ-pdtR2)(µ-pdt)] featuring different combination of dithiolate bridges have been prepared by using dinuclear and mononuclear precursors, [Fe2(CO)6(µ-xdt)] (xdt = pdt, pdtEt2, pdtBn2, adtBn) and [Fe(CO)2(2-dppe)(2-pdt)]. Novel triiron compounds, featuring sterically crowded dithiolate bridges (pdtEt2, pdtBn2), were spectroscopically and structurally characterized. Their protonation and redox behaviours are discussed. The effect of the dithiolate bridges on the electrochemical properties (oxidation and reduction) of the complexes [Fe3(CO)5(2-dppe)(µ-xdt)(µ-pdt)] has been examined by cyclic voltammetry and rationalized by DFT calculations. Studies of the protonation of these species and their proton reduction behaviour were considered.

Four endemic coronaviruses infect humans and cause mild symptoms. Because previous analyses were based on a limited number of sequences and did not control for effects that affect molecular dating, we re-assessed the timing of endemic coronavirus emergence. After controlling for recombination, selective pressure, and molecular clock model, we obtained similar tMRCA (time to the most recent common ancestor) estimates for the four coronaviruses, ranging from 72 (HCoV-229E) to 54 (HCoV-NL63) years ago. The split times of HCoV-229E and HCoV-OC43 from camel alphacoronavirus and bovine coronavirus were dated ~268 and ~99 years ago. The split times of HCoV-HKU1 and HCoV-NL63 could not be calculated, as their zoonoticic sources are unknown. To compare the timing of coronavirus emergence to that of another respiratory virus, we recorded the occurrence of influenza pandemics since 1500. Although there is no clear relationship between pandemic occurrence and human population size, the frequency of influenza pandemics seems to intensify starting around 1700, which corresponds with the initial phase of exponential increase of human population and to the emergence of HCoV-229E. The frequency of flu pandemics in the 19th century also suggests that the concurrence of HCoV-OC43 emergence and the Russian flu pandemic may be due to chance.

Coronaviruses (CoVs) have complex genomes that encode a fixed array of structural and nonstructural components, as well as a variety of accessory proteins that differ even among closely related viruses. Accessory proteins often play a role in the suppression of immune responses and may represent virulence factors. Despite their relevance for CoV phenotypic variability, information on accessory proteins is fragmentary. We applied a systematic approach based on homology detection to create a comprehensive catalogue of accessory proteins encoded by CoVs. Our analyses grouped accessory proteins into 379 orthogroups and 12 super-groups. No orthogroup was shared by the four CoV genera and very few were present in all or most viruses in the same genus, reflecting the dynamic evolution of CoV genomes. We observed differences in the distribution of accessory proteins in CoV genera. Alphacoronaviruses harboured the largest diversity of accessory open reading frames (ORFs), deltacoronaviruses the smallest. However, the average number of accessory proteins per genome was highest in betacoronaviruses. Analysis of the evolutionary history of some orthogroups indicated that the different CoV genera adopted similar evolutionary strategies. Thus, alphacoronaviruses and betacoronaviruses acquired phosphodiesterases and spike-like accessory proteins independently, whereas horizontal gene transfer from reoviruses endowed betacoronaviruses and deltacoronaviruses with fusion-associated small transmembrane (FAST) proteins. Finally, analysis of accessory ORFs in annotated CoV genomes indicated ambiguity in their naming. This complicates cross-communication among researchers and hinders automated searches of large data sets (e.g., PubMed, GenBank). We suggest that orthogroup membership is used together with a naming system to provide information on protein function.

It was recently discovered that some redox proteins can thermodynamically and spatially split two incoming electrons towards different pathways, resulting in the one-electron reduction of two different substrates, featuring reduction potential respectively higher and lower than the parent reductant. This energy conversion process, referred to as electron bifurcation, is relevant not only from a biochemical perspective, but also for the ground-breaking applications that electron-bifurcating molecular devices could have in the field of energy conversion. Natural electron-bifurcating systems contain a two-electron redox centre featuring potential inversion (PI), i. e. with second reduction easier than the first. With the aim of revealing key factors to tailor the span between first and second redox potentials, we performed a systematic density functional study of a 26-molecule set of models with the general formula Fe2 (μ-PR2 )2 (L)6 . It turned out that specific features such as i) a Fe-Fe antibonding character of the LUMO, ii) presence of electron-donor groups and iii) low steric congestion in the Fe's coordination sphere, are key ingredients for PI. In particular, the synergic effects of i)-iii) can lead to a span between first and second redox potentials larger than 700 mV. More generally, the "molecular recipes" herein described are expected to inspire the synthesis of Fe2 P2 systems with tailored PI, of primary relevance to the design of electron-bifurcating molecular devices.

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.

The electron rich Fe2(pdt)(RNC)6 1 (pdt=CH2(CH2S−)2) has been used as starting point for a DFT multi-functional study to assess the feasibility of designing a stable inverted (or rotated) disposition of the two FeL3 pyramidal moieties in the dimetallic core, a key feature of [FeFe]-hydrogenase cofactor. The choice of 1 was motivated by the presence of a rotated form in solution, slightly less stable than the unrotated stereoisomer. Aimed to find an upgraded version of 1, featuring the rotated isomer as ground state, various combinations of factors have been tested, for their effect on the relative stability of rotated vs unrotated isomers. The general result is that combining coordination asymmetry, electron donor presence and isocyanides R substituents able to establish intramolecular interactions is effective in stabilizing the rotated isomer. Our DFT study may inspire the design of synthetic biomimetics, with improved resemblance to the natural system.

The behaviour of triazolylidene ligands coordinated at a {Fe2(CO)5(µ-dithiolate)} core related to the active site of [FeFe]-hydrogenases have been considered to determine whether such carbenes may act as redox electron-reservoirs, with innocent or non-innocent properties. A novel complex featuring a mesoionic carbene (MIC) [Fe2(CO)5(Pmpt)(µ-pdt)] (1; Pmpt = 1-phenyl-3-methyl-4-phenyl-1,2,3-triazol-5-ylidene; pdt = propanedithiolate) was synthesized and characterized by IR, 1H, 13C{1H} NMR spectroscopies, elemental analyses, X-ray diffraction, and cyclic voltammetry. Comparison with the spectroscopic characteristics of its analogue [Fe2(CO)5(Pmbt)(µ-pdt)] (2; Pmbt = 1-phenyl-3-methyl-4-butyl-1,2,3-triazol-5-ylidene) showed the effect of the replacement of a n-butyl by a phenyl group in the 1,2,3-triazole heterocycle. A DFT study was performed to rationalize the electronic behaviour of 1, 2 upon the transfer of two electrons and showed that such carbenes do not behave as redox ligands. With highly perfluorinated carbenes, electronic communication between the di-iron site and the triazole cycle is still limited, suggesting low redox properties of MIC ligands used in this study. Finally, although the catalytic performances of 2 towards proton reduction are weak, the protonation process after a two-electron reduction of 2 was examined by DFT and revealed that the protonation process is favoured by S-protonation but the stabilized diprotonated intermediate featuring a {Fe-H⋯H-S} interaction does not facilitate the release of H2 and may explain low efficiency towards HER (Hydrogen Evolution Reaction).

Despite the high levels of interest in the synthesis of bio-inspired [FeFe]-hydrogenase complexes, H2 oxidation, which is one specific aspect of hydrogenase enzymatic activity, is not observed for most reported complexes. To attempt H-H bond cleavage, two disubstituted diiron dithiolate complexes in the form of [Fe2(μ-pdt)L2(CO)4] (L: PMe3, dmpe) have been used to play the non-biomimetic role of a Lewis base, with frustrated Lewis pairs (FLPs) formed in the presence of B(C6F5)3 Lewis acid. These unprecedented FLPs, based on the bimetallic Lewis base partner, allow the heterolytic splitting of the H2 molecule, forming a protonated diiron cation and hydrido-borate anion. The substitution, symmetrical or asymmetrical, of two phosphine ligands at the diiron dithiolate core induces a strong difference in the H2 bond cleavage abilities, with the FLP based on the first complex being more efficient than the second. DFT investigations examined the different mechanistic pathways involving each accessible isomer and rationalized the experimental findings. One of the main DFT results highlights that the iron site acting as a Lewis base for the asymmetrical complex is the {Fe(CO)3} subunit, which is less electron-rich than the {FeL(CO)2} site of the symmetrical complex, diminishing the reactivity towards H2. Calculations relating to the different mechanistic pathways revealed the presence of a terminal hydride intermediate at the apical site of a rotated {Fe(CO)3} site, which is experimentally observed, and a semi-bridging hydride intermediate from H2 activation at the Fe-Fe site; these are responsible for a favourable back-reaction, reducing the conversion yield observed in the case of the asymmetrical complex. The use of two equivalents of Lewis acid allows for more complete and faster H2 bond cleavage due to the encapsulation of the hydrido-borate species by a second borane, favouring the reactivity of each FLP, in agreement with DFT calculations.

Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease characterized by the loss of the upper and lower motor neurons (MNs). About 10% of patients have a family history (familial, fALS); however, most patients seem to develop the sporadic form of the disease (sALS). SOD1 (Cu/Zn superoxide dismutase-1) is the first studied gene among the ones related to ALS. Mutant SOD1 can adopt multiple misfolded conformation, lose the correct coordination of metal binding, decrease structural stability, and form aggregates. For all these reasons, it is complicated to characterize the conformational alterations of the ALS-associated mutant SOD1, and how they relate to toxicity. In this work, we performed a multilayered study on fibroblasts derived from two ALS patients, namely SOD1L145F and SOD1S135N, carrying the p.L145F and the p.S135N missense variants, respectively. The patients showed diverse symptoms and disease progression in accordance with our bioinformatic analysis, which predicted the different effects of the two mutations in terms of protein structure. Interestingly, both mutations had an effect on the fibroblast energy metabolisms. However, while the SOD1L145F fibroblasts still relied more on oxidative phosphorylation, the SOD1S135N fibroblasts showed a metabolic shift toward glycolysis. Our study suggests that SOD1 mutations might lead to alterations in the energy metabolism.

Four coronaviruses (HCoV-OC43, HCoV-HKU1, HCoV-NL63, and HCoV-229E) are endemic in human populations. All these viruses are seasonal and generate short-term immunity. Like the highly pathogenic coronaviruses, the endemic coronaviruses have zoonotic origins. Thus, understanding the evolutionary dynamics of these human viruses might provide insight into the future trajectories of SARS-CoV-2 evolution. Because the zoonotic sources of HCoV-OC43 and HCoV-229E are known, we applied a population genetics–phylogenetic approach to investigate which selective events accompanied the divergence of these viruses from the animal ones. Results indicated that positive selection drove the evolution of some accessory proteins, as well as of the membrane proteins. However, the spike proteins of both viruses and the hemagglutinin-esterase (HE) of HCoV-OC43 represented the major selection targets. Specifically, for both viruses, most positively selected sites map to the receptor-binding domains (RBDs) and are polymorphic. Molecular dating for the HCoV-229E spike protein indicated that RBD Classes I, II, III, and IV emerged 3–9 years apart. However, since the appearance of Class V (with much higher binding affinity), around 25 years ago, limited genetic diversity accumulated in the RBD. These different time intervals are not fully consistent with the hypothesis that HCoV-229E spike evolution was driven by antigenic drift. An alternative, not mutually exclusive possibility is that strains with higher affinity for the cellular receptor have out-competed strains with lower affinity. The evolution of the HCoV-OC43 spike protein was also suggested to undergo antigenic drift. However, we also found abundant signals of positive selection in HE. Whereas such signals might result from antigenic drift, as well, previous data showing co-evolution of the spike protein with HE suggest that optimization for human cell infection also drove the evolution of this virus. These data provide insight into the possible trajectories of SARS-CoV-2 evolution, especially in case the virus should become endemic.

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.

The potentials of redox systems involving nitrogen, oxygen, and metal ions of the first-row transition series have been computed according to the general approach of the grand canonical ensemble, which leads to the equilibrium value of the reduction potential via a (complete) sampling of configuration space at a given temperature. The approach is a single configuration approach in the sense that identical molecular structures are sampled for both the oxidized and reduced species considered in water solution. In this study, the solute and a cluster of 11-12 water molecules are treated explicitly at the same level of theory and embedded in a continuum solvent. The molecular energies are computed in the framework of the density functional theory. Our approach is basically different from the approach based on the ThermoDynamic Cycle involving gas-phase calculations of the electron affinity of the oxidized species, corrected by the differential hydration energy (obtained from continuum solvent models only) between oxidized and reduced forms. The calculated redox potentials are in agreement with the available experimental data much closer than other results so far presented in the literature. Our results are very satisfactory also in the case of the 3+/2+ redox states of the first-row transition metals, i.e., systems with a high positive charge for which enhanced effects of the solvent are expected.

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.

In view of the depletion of fossil fuel reserves and climatic effects of greenhouse gas emissions, Ni,Fe-containing carbon monoxide dehydrogenase (Ni-CODH) enzymes have attracted increasing interest in recent years for their capability to selectively catalyze the reversible reduction of CO2 to CO (CO2 + 2H+ + 2e- ⇌ CO + H2O). The possibility of converting the greenhouse gas CO2 into useful materials that can be used as synthetic building blocks or, remarkably, as carbon fuels makes Ni-CODH a very promising target for reverse-engineering studies. In this context, in order to provide insights into the chemical principles underlying the biological catalysis of CO2 activation and reduction, quantum mechanics calculations have been carried out in the framework of density functional theory (DFT) on different-sized models of the Ni-CODH active site. With the aim of uncovering which stereoelectronic properties of the active site (known as the C-cluster) are crucial for the efficient binding and release of CO2, different coordination modes of CO2 to different forms and redox states of the C-cluster have been investigated. The results obtained from this study highlight the key role of the protein environment in tuning the reactivity and the geometry of the C-cluster. In particular, the protonation state of His93 is found to be crucial for promoting the binding or the dissociation of CO2. The oxidation state of the C-cluster is also shown to be critical. CO2 binds to Cred2 according to a dissociative mechanism (i.e., CO2 binds to the C-cluster after the release of possible ligands from Feu) when His93 is doubly protonated. CO2 can also bind noncatalytically to Cred1 according to an associative mechanism (i.e., CO2 binding is preceded by the binding of H2O to Feu). Conversely, CO2 dissociates when His93 is singly protonated and the C-cluster is oxidized at least to the Cint redox state.

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.*

Objective: Friedreich ataxia (FRDA) is an inherited neurological disease defined by progressive movement incoordination. We undertook a comprehensive characterization of the spatial profile and progressive evolution of structural brain abnormalities in people with FRDA. Methods: A coordinated international analysis of regional brain volume using magnetic resonance imaging data charted the whole-brain profile, interindividual variability, and temporal staging of structural brain differences in 248 individuals with FRDA and 262 healthy controls. Results: The brainstem, dentate nucleus region, and superior and inferior cerebellar peduncles showed the greatest reductions in volume relative to controls (Cohen d= 1.5–2.6). Cerebellar gray matter alterations were most pronounced in lobules I–VI (d= 0.8), whereas cerebral differences occurred most prominently in precentral gyri (d= 0.6) and corticospinal tracts (d= 1.4). Earlier onset age predicted less volume in the motor cerebellum (rmax= 0.35) and peduncles (rmax= 0.36). Disease duration and severity correlated with volume deficits in the dentate nucleus region, brainstem, and superior/inferior cerebellar peduncles (rmax= −0.49); subgrouping showed these to be robust and early features of FRDA, and strong candidates for further biomarker validation. Cerebral white matter abnormalities, particularly in corticospinal pathways, emerge as intermediate disease features. Cerebellar and cerebral gray matter loss, principally targeting motor and sensory systems, preferentially manifests later in the disease course. Interpretation: FRDA is defined by an evolving spatial profile of neuroanatomical changes beyond primary pathology in the cerebellum and spinal cord, in line with its progressive clinical course. The design, interpretation, and generalization of research studies and clinical trials must consider neuroanatomical staging and associated interindividual variability in brain measures. ANN NEUROL 2021;90:570–583.

Substitution of CO ligands by PPh3 in Fe2(μ-S2)(CO)6 proceeds by a desulfurization–resulfurization sequence, generating SPPh3 and Fe2(μ-S)(CO)6(PPh3)2 as intermediates. Protonation of Fe2(μ-S)(CO)6(PPh3)2 occurs at sulfur.

A few bio-inorganic systems have been studied by means of modern quantum chemistry (QM) methods, such as the Density Functional Theory (DFT) in connection with a large set of basis functions. At this level, DFT has proven to give reliable (semi-quantitative) description of several properties of transition metals complexes which are either relevant part of a natural enzyme or ad hoc built to mimic the behaviour of enzymes. The first example considered is the N,N'-ethylenebis(acetylacetonatiminato)Co(II) (Coacacen), a very famous synthetic oxygen carrier. We report results of a DFT investigation of Coacacen in its free form as well as in penta-coordinated form with a suitable axial ligand and, finally, in hexa-coordinated form bound to dioxygen. The problems related to the electronic structure of Coacacen derivatives are very old, and have been investigated (mainly experimentally) for several years. Coacacen has been the first bio-inorganic system investigated in the group of Renato Ugo in the 1970s. In addition, a short review will be presented concerning the “modern” problems of the bio-inorganics, as they are presently investigated in our research group based at the University of Milano-Bicocca (Italy): the catalytic cycle characteristic of Fe-Fe hydrogenases and the model compounds describing the interaction between copper and amyloid β-peptides.

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; The electrochemical reduction of complexes [Fe2(CO)4(k2‐phen)(μ‐xdt)] (phen = 1,10‐phenanthroline ; xdt = pdt (1), adtiPr (2)) in MeCN‐[Bu4N][PF6] 0.2 M is described as a two‐reduction process. DFT calculations show that 1 and its reduced form 1‐ display metal‐ and phenanthroline‐centered frontier orbitals (LUMO and SOMO) indicating the non‐innocence of the phenanthroline ligand. Two energetically close geometries were found for the doubly reduced species suggesting an intriguing influence of the phenanthroline ligand leading to the cleavage of a Fe‐S bond as proposed generally for this type of complex or retaining the electron density and avoiding Fe‐S cleavage. Extension of calculations to other complexes with edt, adtiPr bridge and even virtual species [Fe2(CO)4(k2‐phen)(μ‐adtR)] (R = CH(CF3)2, H) or [Fe2(CO)4(k2‐phen)(μ‐pdtR)] (R = CH(CF3)2, iPr) showed that the relative stability between both two‐electron‐reduced isomers depends on the nature of the bridge and the possibility to establish a remote anagostic interaction between the iron centre {Fe(CO)3} and the group carried by the bridged‐head atom of the dithiolate group.

Palmitoylethanolamide (PEA) belongs to the class of N-acylethanolamine and is an endogenous lipid potentially useful in a wide range of therapeutic areas, products containing PEA are licensed for use in humans as a nutraceutical, a food supplement, or food for medical purposes for its analgesic and anti-inflammatory properties demonstrating efficacy and tolerability. However, the exogenously administered PEA is rapidly inactivated, in this process, fatty acid amide hydrolase (FAAH) plays a key role both in hepatic metabolism and in intracellular degradation. So, the aim of the present study was the design and synthesis of PEA analogues that are more resistant to FAAH-mediated hydrolysis. A small library of PEA analogues was designed and tested by molecular docking and density functional theory calculations to find the more stable analogue. The computational investigation identified RePEA as the best candidate in terms of both synthetic accessibility and metabolic stability to FAAH-mediated hydrolysis. The selected compound was synthesized and assayed ex vivo to monitor FAAH-mediated hydrolysis and to confirm its anti-inflammatory properties. 1H-NMR spectroscopy performed on membrane samples containing FAAH in integral membrane protein demonstrated that RePEA is not processed by FAAH, in contrast with PEA. Moreover, RePEA retains PEA&rsquo, s ability to inhibit LPS-induced cytokine release in both murine N9 microglial cells and human PMA-THP-1 cells.

International audience; Electrochemical oxidation of the complex [Fe2(CO)4(κ2‐dmpe)(µ‐adtBn)] (adtBn = (SCH2)2NCH2C6H5, dmpe = Me2PCH2CH2PMe2) (1) has been studied by cyclic voltammetry (CV) in acetonitrile and in dichloromethane in presence of various substrates L (L =MeCN, trimethylphosphite, isocyanide). The oxidized species, [1‐MeCN](PF6)2, [1‐(P(OMe)3)2](PF6)2 and [1‐(RNC)4](PF6)2 (R = tButyl, Xylyl), have been prepared and characterized by IR, NMR spectroscopies and, excepted [1‐MeCN](PF6)2, by X‐ray diffraction analysis. The crystallographic structures of the new FeIIFeII complexes reveal in any case that the association of one additional ligand (P(OMe)3 or RNC) occurs and, according to the nature of the substrates, further substitutions of one or three carbonyl groups, by P(OMe)3 or RNC, respectively, arise. Density functional theory (DFT) calculations have been performed for elucidating and discriminating, in each case, the mechanisms leading to the corresponding oxidized species. Moreover, the different degree of ligand substitution in the diiron core has been theoretically rationalized.

The pineal gland can be involved in a variety of neoplastic and congenital masses and tumors. Pineal gland neoplasms occur more frequently in children, accounting for 3–8% of intracranial tumors in the pediatric population. Pineal cysts are small lesions usually asymptomatic and encountered incidentally. Pathologic processes involving the pineal region produce signs and symptoms related to the mass effect on the adjacent structures and invasion of surrounding structures. These include several acute symptoms, such as increased intracranial pressure syndrome from obstruction of the aqueduct and consequent hydrocephalus, and Parinaud syndrome. Pineal apoplexy is rare and refers to the sudden neurological deterioration following hemorrhage in the pineal gland, most commonly into a pineal cyst. Knowledge of the clinical presentation and imaging features of these lesions is essential to narrow the differential diagnosis, especially when presenting with acute onset.