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Many proteins exist naturally as symmetrical homooligomers or homopolymers 1 . The emergent structural and functional properties of such protein assemblies have inspired extensive efforts in biomolecular design 2 – 5 . As synthesized by ribosomes, proteins are inherently asymmetric. Thus, they must acquire multiple surface patches that selectively associate to generate the different symmetry elements needed to form higher-order architectures 1 , 6 —a daunting task for protein design. Here we address this problem using an inorganic chemical approach, whereby multiple modes of protein–protein interactions and symmetry are simultaneously achieved by selective, ‘one-pot’ coordination of soft and hard metal ions. We show that a monomeric protein (protomer) appropriately modified with biologically inspired hydroxamate groups and zinc-binding motifs assembles through concurrent Fe 3+ and Zn 2+ coordination into discrete dodecameric and hexameric cages. Our cages closely resemble natural polyhedral protein architectures 7 , 8 and are, to our knowledge, unique among designed systems 9 – 13 in that they possess tightly packed shells devoid of large apertures. At the same time, they can assemble and disassemble in response to diverse stimuli, owing to their heterobimetallic construction on minimal interprotein-bonding footprints. With stoichiometries ranging from [2 Fe:9 Zn:6 protomers] to [8 Fe:21 Zn:12 protomers], these protein cages represent some of the compositionally most complex protein assemblies—or inorganic coordination complexes—obtained by design. An inorganic chemical approach to biomolecular design is used to generate ‘cages’ that can simultaneously promote symmetry and multiple modes of protein interactions.

The Fe–S clusters of nitrogenases carry out the life-sustaining conversion of N2 to NH3. Although progress continues to be made in modelling the structural features of nitrogenase cofactors, no synthetic Fe–S cluster has been shown to form a well-defined coordination complex with N2. Here we report that embedding an [MoFe3S4] cluster in a protective ligand environment enables N2 binding at Fe. The bridging [MoFe3S4]2(μ-η1:η1-N2) complex thus prepared features a substantially weakened N–N bond despite the relatively high formal oxidation states of the metal centres. Substitution of one of the [MoFe3S4] cubanes with an electropositive Ti metalloradical induces additional charge transfer to the N2 ligand with generation of Fe–N multiple-bond character. Structural and spectroscopic analyses demonstrate that N2 activation is accompanied by shortened Fe–S distances and charge transfer from each Fe site, including those not directly bound to N2. These findings indicate that covalent interactions within the cluster play a critical role in N2 binding and activation.Although iron–sulfur cofactors are known to carry out biological nitrogen fixation, how these clusters bind dinitrogen remains poorly understood. Now, a dinitrogen complex of a synthetic iron–sulfur cluster has been characterized, and electronic cooperation in the cluster has been shown to result in strong N–N bond activation.

The electronic structure of the nitrogenase metal cofactors is central to nitrogen fixation. However, the P-cluster and FeMo cofactor, each containing eight Fe atoms, have eluded detailed characterization of their electronic properties. We report on the low-energy electronic states of the P-cluster in three oxidation states through exhaustive many-electron wavefunction simulations enabled by new theoretical methods. The energy scales of orbital and spin excitations overlap, yielding a dense spectrum with features that we trace to the underlying atomic states and recouplings. The clusters exist in superpositions of spin configurations with non-classical spin correlations, complicating interpretation of magnetic spectroscopies, whereas the charges are mostly localized from reorganization of the cluster and its surroundings. On oxidation, the opening of the P-cluster substantially increases the density of states, which is intriguing given its proposed role in electron transfer. These results demonstrate that many-electron simulations stand to provide new insights into the electronic structure of the nitrogenase cofactors. The electronic structures of the metal cofactors of nitrogenase are key to biological nitrogen fixation; however, the [Fe 8 S 7 ] P-cluster and FeMo cofactor have eluded detailed electronic characterization. Now, the electronic structure of the P-cluster of nitrogenase has been revealed at the many-electron level through exhaustive quantum wavefunction simulations.

Hydrogen production through water splitting is one of the most promising solutions for the storage of renewable energy. [NiFe] hydrogenases are organometallic enzymes containing nickel and iron centres that catalyse hydrogen evolution with performances that rival those of platinum. These enzymes provide inspiration for the design of new molecular catalysts that do not require precious metals. However, all heterodinuclear NiFe models reported so far do not reproduce the Ni-centred reactivity found at the active site of [NiFe] hydrogenases. Here, we report a structural and functional NiFe mimic that displays reactivity at the Ni site. This is shown by the detection of two catalytic intermediates that reproduce structural and electronic features of the Ni-L and Ni-R states of the enzyme during catalytic turnover. Under electrocatalytic conditions, this mimic displays high rates for H 2 evolution (second-order rate constant of 2.5 × 10 4  M −1  s −1 ; turnover frequency of 250 s −1 at 10 mM H + concentration) from mildly acidic solutions. [NiFe] hydrogenases are enzymes containing nickel and iron centres that catalyse hydrogen evolution with performances that rival those of platinum catalysts. Now, a NiFe model complex has been reported that mimics the structure and the Ni-centred hydrogen evolution activity found at the active site of [NiFe] hydrogenases.

Protein catalysis requires the atomic-level orchestration of side chains, substrates and cofactors, and yet the ability to design a small-molecule-binding protein entirely from first principles with a precisely predetermined structure has not been demonstrated. Here we report the design of a novel protein, PS1, that binds a highly electron-deficient non-natural porphyrin at temperatures up to 100 °C. The high-resolution structure of holo-PS1 is in sub-Å agreement with the design. The structure of apo-PS1 retains the remote core packing of the holoprotein, with a flexible binding region that is predisposed to ligand binding with the desired geometry. Our results illustrate the unification of core packing and binding-site definition as a central principle of ligand-binding protein design. The first demonstration of a protein designed entirely from first principles that binds a small-molecule cofactor in a precisely predetermined orientation has now been described. The design method utilizes a remote protein core that both anchors and predisposes a flexible binding site for the desired cofactor-binding geometry.

Iron nitrides are key intermediates in biological nitrogen fixation and the industrial Haber–Bosch process, used to form ammonia from dinitrogen. However, the proposed successive conversion of nitride to ammonia remains elusive. In this regard, the search for well-described multi-iron nitrido model complexes and investigations on controlling their reactivity towards ammonia formation have long been of great challenge and importance. Here we report a well-defined thiolate-bridged Fe IV Fe IV μ-nitrido complex featuring an uncommon bent Fe–N–Fe moiety. Remarkably, this complex shows excellent reactivity toward hydrogenation with H 2 at ambient conditions, forming ammonia in high yield. Combined experimental and computational studies demonstrate that a thiolate-bridged Fe III Fe III μ-amido complex is a key intermediate, which is generated through an unusual two-electron oxidation of H 2 . Moreover, ammonia production was also realized by treating this diiron μ-nitride with electrons and water as a proton source. Multi-iron nitrides are implicated as potential key intermediates in biological nitrogen fixation and the industrial Haber–Bosch process, but well-described functional model systems are rare. Now, a well-defined thiolate-bridged Fe IV Fe IV μ-nitrido complex has been found to show excellent reactivity toward hydrogenation with H 2 through a stepwise pathway to form ammonia in high yield.

Selective metal coordination is central to the functions of metalloproteins:1,2 each metalloprotein must pair with its cognate metallocofactor to fulfl its biological role3 . However, achieving metal selectivity solely through a three-dimensional protein structure is a great challenge, because there is a limited set of metal-coordinating amino acid functionalities and proteins are inherently fexible, which impedes steric selection of metals3,4 . Metal-binding afnities of natural proteins are primarily dictated by the electronic properties of metal ions and follow the Irving–Williams series5 (Mn2+ < Fe2+ < Co2+ < Ni2+  Zn2+) with few exceptions6,7 . Accordingly, metalloproteins overwhelmingly bind Cu2+ and Zn2+ in isolation, regardless of the nature of their active sites and their cognate metal ions1,3,8 . This led organisms to evolve complex homeostatic machinery and non-equilibrium strategies to achieve correct metal speciation1,3,8–10. Here we report an artifcial dimeric protein, (AB)2, that thermodynamically overcomes the Irving–Williams restrictions in vitro and in cells, favouring the binding of lower-Irving–Williams transition metals over Cu2+, the most dominant ion in the Irving–Williams series. Counter to the convention in molecular design of achieving specifcity through structural preorganization, (AB)2 was deliberately designed to be fexible. This fexibility enabled (AB)2 to adopt mutually exclusive, metal-dependent conformational states, which led to the discovery of structurally coupled coordination sites that disfavour Cu2+ ions by enforcing an unfavourable coordination geometry. Aside from highlighting fexibility as a valuable element in protein design, our results illustrate design principles for constructing selective metal sequestration agents.

Significant progress has been made in the bioinorganic modeling of the paramagnetic states believed to be involved in the hydrogen redox chemistry catalyzed by [NiFe] hydrogenase. However, the characterization and isolation of intermediates involved in mononuclear Ni electrocatalysts which are reported to operate through a Ni I/III cycle have largely remained elusive. Herein, we report a Ni II complex (NCHS2)Ni(OTf)2, where NCHS2 is 3,7-dithia-1(2,6)-pyridina-5(1,3)-benzenacyclooctaphane, that is an efficient electrocatalyst for the hydrogen evolution reaction (HER) with turnover frequencies of ~3,000 s −1 and a overpotential of 670 mV in the presence of trifluoroacetic acid. This electrocatalyst follows a hitherto unobserved HER mechanism involving C-H activation, which manifests as an inverse kinetic isotope effect for the overall hydrogen evolution reaction, and Ni I /Ni III intermediates, which have been characterized by EPR spectroscopy. We further validate the possibility of the involvement of Ni III intermediates by the independent synthesis and characterization of organometallic Ni III complexes. The characterization of nickel (Ni)‐centred paramagnetic states relevant to [NiFe] hydrogenases is rare in mononuclear Ni hydrogen evolution catalysts. Here, the authors report the spectroscopic and synthetic characterization of Ni I and Ni III states in an organometallic Ni hydrogen evolution catalyst.

Designing metal sites into de novo proteins has significantly improved, recently. However, identifying the minimal coordination spheres, able to encompass the necessary information for metal binding and activity, still represents a great challenge, today. Here, we test our understanding with a benchmark, nevertheless difficult, case. We assemble into a miniature 28-residue protein, the quintessential elements required to fold properly around a FeCys 4 redox center, and to function efficiently in electron-transfer. This study addresses a challenge in de novo protein design, as it reports the crystal structure of a designed tetra-thiolate metal-binding protein in sub-Å agreement with the intended design. This allows us to well correlate structure to spectroscopic and electrochemical properties. Given its high reduction potential compared to natural and designed FeCys 4 -containing proteins, we exploit it as terminal electron acceptor of a fully artificial chain triggered by visible light. Living organisms regulate their energy demand by managing electron trafficking in complex transport chains. Here, the authors pioneer a fully artificial electron chain triggered by visible light using designed proteins, unlocking possibilities in bioengineering.

The nitrogen cycle is one of the most important biogeochemical cycles on Earth because nitrogen is an essential nutrient for all life forms. To supplement natural nitrogen fixation, farmers add large amounts of nitrogen-containing fertilizer to their soils such that nitrogen never becomes a limiting nutrient for plant growth. However, of the nitrogen added to fields — most of which is in the form of NH 3 and NO 3 − — only 30–50% is taken up by plants, while the remainder is metabolized by soil microorganisms in processes with detrimental environmental impacts. The first of these processes, that is, nitrification, refers to the biological oxidation of NH 3 to NO 2 − and NO 3 − , which have low retention in soil and pollute waterways, leading to downstream eutrophication and ultimately ‘dead zones’ (low oxygen zones) in coastal waters, for example, the Gulf of Mexico. In a second process, namely, denitrification, NO 3 − and NO 2 − undergo stepwise reduction to N 2 O and N 2 . Substantial amounts of the N 2 O produced in this process escape into the atmosphere, contributing to climate change and ozone destruction. Recent results suggest that nitrification also affords N 2 O. This Review describes the enzymes involved in NH 3 oxidation and N 2 O production and degradation in the nitrogen cycle. We pay particular attention to the active site structures, the associated coordination chemistry that enables the chemical transformations and the reaction mechanisms. Nitrification and denitrification are responsible for the processing of ammonia fertilizer, ultimately leading to the generation of environmental pollutants that accumulate in waterways and the atmosphere. This Review describes the enzymes involved in these processes, which fascinate with their unusual active sites and the surprising reactions that they catalyse.