Chemical bonding, traditionally being the language of chemists, gives a wealth of intuitive shortcuts in understanding structure, properties, and reactivity of molecules. An analogous language based on structure or even just formula of materials would give tremendous advantage in materials discovery and rational tuning of their properties. The present perspective focuses on the “local”, chemical approaches to rationalizing the chemical bonding in materials. The “divide” part of the approach consists of isolating relevant small fragments from the solid, either through electron localization schemes or through directly considering small cluster fragments possessing bonding elements of the solid. The fragment is analyzed with state-of-the-art theory and experiment. Once the local bonding elements in the small unit and their relationship to structure and possible properties are realized, they get supplemented with energy content and mapped back onto the material, eventually enabling strategic modifications and materials design. This constitutes the “conquer” part of the strategy. Several examples are presented when such chemical bonding analyses allowed the predictions of broader materials families than previously known. Discussed applications include surface alloys for catalysis, ultrahard bulk alloys, and 2D materials with interesting conductivities and magnetism.

While boride clusters of alkali and transition metals have been observed and extensively characterized, so far little is known about lanthanide–boron clusters. Lanthanide–boride solids are intriguing, however, and therefore it is of interest to understand the fundamental electronic properties of such systems, also on the subnano scale. We report a joint experimental photoelectron spectroscopic and theoretical study of the SmB6– anion, iso-stoichiometric to the SmB6 solid—a topological Kondo insulator. The cluster is found to feature strong static and dynamic electron correlations and relativistic components, calling for treatment with CASPT2 and up sixth-order Douglass–Kroll–Hess (DKH) relativistic correction. The cluster has a C2v structure and covalent Sm–B bonds facilitated by f atomic orbitals on Sm, which are typically thought to be contracted and inert. Additionally, the cluster retains the double antiaromaticity of the B62– cluster.

Electrostatic preorganization is thought to be a principle factor responsible for the impressive catalytic capabilities of enzymes. The full protein structure is believed to facilitate catalysis by exerting a highly specific electrostatic field on the active site. Computationally determining the extent of electrostatic preorganization is a challenging process. We propose using the topology and geometry of the electron charge density in the enzyme's active site to asses the effects of electrostatic preorganization. In support of this approach we study the convergence of features of the charge density as the size of the active site model increases in Histone Deacetylase 8. The magnitude of charge density at critical points and most Bader atomic charges are found to converge quickly as more of the protein is included in the simulation. The exact position of critical points however, is found to converge more slowly and be strongly influenced by the protein residues that are further away from the active site. We conjecture that the positions of critical points are affected through perturbations to the wavefunctions in the active site caused by dipole moments from amino acid residues throughout the protein. We further hypothesize that electrostatic preorganization, from the point of view of charge density, can not be easily understood through the charges on atoms or the nature of the bonding interactions, but through the relative positions of critical points that are known to correlate with reactivity and reaction barriers.

We present a systematic investigation of the influence of theoretical parameters on the characterization of surface and subsurface oxygen vacancies in anatase with the 101 facet exposed. This metastable phase of titania continues to resist a facile description of its defects, particularly, in the reduced state. Nine nonequivalent sites were examined under varying levels of theory with characterization of formation energies, geometry, and electronic states extracted from Bader charges, charge density, and density of states. At DFT+U levels of theory, these sites remain nonequivalent. We note a new surface oxygen vacancy minimum related to localization of electrons at surface and a subsurface Ti atoms, rather than the more favorable localization at neighboring surface Ti atoms.

We first report a global optimization approach based on GPU accelerated Deep Neural Network (DNN) fitting, for modeling metal clusters at realistic temperatures. The seven-layer multidimensional and locally connected DNN is combined with limited-step Density Functional Theory (DFT) geometry optimization to reduce the time cost of full DFT local optimization, which is considered to be the most time-consuming step in global optimization. An algorithm based on bond length distribution analysis is used to efficiently sample the configuration space and generate random initial structures. A structure similarity measurement method based on depth-first search is used to identify duplicates. The performance of the new approach is examined by the application to the global minimum searching for Pt9 and Pt13. The ensemble-average representations of the two clusters are constructed based on all geometrically different isomers, on which the structure transition is predicted at low and high temperatures, for Pt9 and Pt13 clusters, respectively. Finally, the ensemble-averaged vertical ionization potential changes when temperature increases, and the property in conditions of catalysis can be different from that evaluated at the global minimum structure.

Transition-metal hydrides represent a unique class of compounds, which are essential for catalysis, organic synthesis, and hydrogen storage. In this work we study IrH5(PPh3)2, (RuH5(PiPr3)2)−, (OsH5(PiPr3)2)−, and OsH4(PPhMe2)3 polyhydride complexes, inspired by the recent discovery of the σ-aromatic PtZnH5− cluster anion. The distinctive feature of these molecules is that, like in the PtZnH5− cluster, the metal is five-fold coordinated in-plane, and holds additional ligands at the axial positions. This work shows that the unusual coordination in these compounds indeed can be explained by σ-aromaticity in the pentagonal arrangement, stabilized by the atomic orbitals on the metal. Based on this newly elucidated bonding principle, we additionally propose a new family of polyhydrides that display a uniquely high coordination. We also report the first indications of how aromaticity may impact the reactivity of these molecules.

Histone deacetylases (HDACs) are responsible for the removal of acetyl groups from histones, resulting in gene silencing. Overexpression of HDACs is associated with cancer, and their inhibitors are of particular interest as chemotherapeutics. However, HDACs remain a target of mechanistic debate. HDAC class 8 is the most studied HDAC, and of particular importance due to its human oncological relevance. HDAC8 has traditionally been considered to be a Zn-dependent enzyme. However, recent experimental assays have challenged this assumption and shown that HDAC8 is catalytically active with a variety of different metals, and that it may be a Fe-dependent enzyme in vivo. We studied two opposing mechanisms utilizing a series of divalent metal ions in physiological abundance (Zn2+, Fe2+, Co2+, Mn2+, Ni2+, and Mg2+). Extensive sampling of the entire protein with different bound metals was done with the mixed quantum-classical QM/DMD method. Density functional theory (DFT) on an unusually large cluster model was used to describe the active site and reaction mechanism. We have found that the reaction profile of HDAC8 is similar among all metals tested, and follows one of the previously published mechanisms, but the rate-determining step is different from the one previously claimed. We further provide a scheme for estimating the metal binding affinities to the protein. We use the quantum theory of atoms in molecules (QTAIM) to understand the different binding affinities for each metal in HDAC8 as well as the ability of each metal to bind and properly orient the substrate for deacetylation. The combination of this data with the catalytic rate constants is required to reproduce the experimentally observed trend in metal-depending performance. We predict Co2+ and Zn2+ to be the most active metals in HDAC8, followed by Fe2+, and Mn2+ and Mg2+ to be the least active.

The top monolayers of surface carbides and nitrides of Co and Ni are predicted to yield new stable 2D materials upon exfoliation. These 2D phases are p4g clock reconstructed, and contain planar tetracoordinated C or N. The stability of these flat carbides and nitrides is high, and ab initio molecular dynamics at a simulation temperature of 1800 K suggest that the materials are thermally stable at elevated temperatures. The materials owe their stability to local triple aromaticity (π, σ-radial, and σ-peripheral) associated with binding of the main group element to the metal. All predicted 2D phases are conductors, and the two alloys of Co are also ferromagnetic, a property especially rare among 2D materials. The preparation of 2D carbides and nitrides is envisioned to be done through surface deposition and peeling, possibly on a metal with a larger lattice constant for reduced affinity.

Immobilized Pt clusters are interesting catalysts for dehydrogenation of alkanes. However, surface-deposited Pt clusters deactivate rapidly via sintering and coke deposition. The results reported here suggest that adding boron to oxide-supported Pt clusters could be a “magic bullet” against both means of deactivation. The model systems studied herein are pure and B-doped Pt clusters deposited on MgO(100). The nonstoichiometric boride cluster obtained via such alloying is found to anchor to the support via a covalent B–O bond, and the cluster-surface binding is much stronger than in the case of pure Pt clusters. Additionally, B introduces covalency to the intracluster bonding, leading to structural distortion and stabilization. The energy required to dissociate a Pt atom from a boride cluster is significantly larger than that of pure Pt clusters. These energetic arguments lead to the proposal that sintering via both Ostwald ripening and particle coalescence would be discouraged relative to pure Pt clusters. Finally, it is shown that the affinity to C also drops dramatically for borated clusters, discouraging coking and increasing the selectivity of potential cluster catalysts.Keywords: alloying; coking; density functional theory; PtB clusters on magnesia; sintering

Global optimization techniques for molecules, solids, and clusters are numerous and can be algorithmically elegant. Yet many of them are time-consuming and prone to getting trapped in local minima. Among the available methods, Coalescence Kick (CK) is attractive: it combines a nearly insulting simplicity with thoroughness. A new version of CK is reported here, called Adaptive Force-Field-Assisted Coalescence Kick (AFFCK). The generation of stationary points on the potential energy surface is tremendously accelerated as compared to that of the earlier, pure ab initio CK, through the introduction of an intermediate step where structures are optimized using a classical force field (FF). The FF itself is system-specific, developed on-the-fly within the algorithm. The pre-computed energies resulting from the FF step are found to be surprisingly indicative of energies in subsequent Density Functional Theory optimization, which enables AFFCK to effectively screen thousands of initial CK-generated structures for favorable starting geometries. Additionally, AFFCK incorporates the use of symmetry operations in order to enhance the diversity in the search space, increase the chance for highly symmetric structures to appear, and speed up convergence of optimizations. A structure-recognition routine ensures diversity in the search space by preventing multiple copies of the same starting geometry from being generated and run. The tests show that AFFCK is much faster than traditional ab initio-only CK. We applied AFFCK to the search for global and low-energy local minima of gas-phase clusters of boron and platinum. For Pt8 a new global minimum structure is found, which is significantly lower in energy than previously reported Pt8 minima. Although AFFCK confirms the global minima of B5–, B8, and B9–, it proves to be less efficient for systems with nontrivial bonding.

Correction for ‘Pure and Zn-doped Pt clusters go flat and upright on MgO(100)’ by Lu Shen et al., Phys. Chem. Chem. Phys., 2014, 16, 26436–26442.

The mechanism of the formation of coumarins via the Pd-catalyzed intramolecular hydroarylation of the C–C triple bond is elucidated computationally, in corroboration with experimental data. It is shown that the reaction follows the concerted metalation–deprotonation (CMD) mechanism. The typically suspected mechanisms of ambiphilic metal ligand activation (AMLA), electrophilic aromatic substitution (EAS), and oxidative addition (OA) are suggested to be non-competitive, based on predicted conformations and energetics. Two forms of the Pd catalysts are used: Pd(OAc)2, and Pd(TFA)2. The predicted activation free energy barrier for the TFA-based catalyst is lower, both in the gas phase and in the CH2Cl2 solvent, in agreement with the experimental observations. Adding electron-withdrawing groups to the catalyst assists the first and rate-limiting step of the reaction, the deprotonation of the aromatic ring, as understood through charge analysis.

Metalloproteins present a considerable challenge for modeling, especially when the starting point is far from thermodynamic equilibrium. Examples include formidable problems such as metalloprotein folding and structure prediction upon metal addition, removal, or even just replacement; metalloenzyme design, where stabilization of a transition state of the catalyzed reaction in the specific binding pocket around the metal needs to be achieved; docking to metal-containing sites and design of metalloenzyme inhibitors. Even more conservative computations, such as elucidations of the mechanisms and energetics of the reaction catalyzed by natural metalloenzymes, are often nontrivial. The reason is the vast span of time and length scales over which these proteins operate, and thus the resultant difficulties in estimating their energies and free energies. It is required to perform extensive sampling, properly treat the electronic structure of the bound metal or metals, and seamlessly merge the required techniques to assess energies and entropies, or their changes, for the entire system. Additionally, the machinery needs to be computationally affordable. Although a great advancement has been made over the years, including some of the seminal works resulting in the 2013 Nobel Prize in chemistry, many aforementioned exciting applications remain far from reach. We review the methodology on the forefront of the field, including several promising methods developed in our lab that bring us closer to the desired modern goals. We further highlight their performance by a few examples of applications.

Molecular orbitals (MOs), while one of the most widely used representations of the electronic structure of a system, are often too complex to intuit properties. Aside from the simplest of cases, it is not necessarily possible to visually tell which orbitals are bonding or antibonding along particular directions, especially in cases of highly delocalized and nontrivial bonding like metal clusters or solids. We propose a method for easily assessing and comparing the relative bonding contributions of MOs, by calculating their response to stress (e.g., compression). We find that this approach accurately describes relative bonding or antibonding character in both the simplest cases and provides new insight in more complex cases. We test the approach on four systems: H2, Am2, benzene, and the Pt4 cluster. In exploring this methodology, a scheme became elucidated, for predicting changes in the ground electronic configuration upon compression, including changes in bonding order, angular momenta of occupied MOs, and trends in MO ordering. We note that the applications of this work go beyond simple molecules and could be straightforwardly extended to, for example, solids and their response to stress along the specific crystallographic plane. Additionally, predictions of structures and properties of chemical systems under stress could result from the emerging intuition about changes in the electronic structure.

Natural metalloenzymes are often the most proficient catalysts in terms of their activity, selectivity, and ability to operate at mild conditions. However, metalloenzymes are occasionally surprising in their selection of catalytic metals, and in their responses to metal substitution. Indeed, from the isolated standpoint of producing the best catalyst, a chemist designing from first-principles would likely choose a different metal. For example, some enzymes employ a redox active metal where a simple Lewis acid is needed. Such are several hydrolases. In other cases, substitution of a non-native metal leads to radical improvements in reactivity. For example, histone deacetylase 8 naturally operates with Zn2+ in the active site but becomes much more active with Fe2+. For β-lactamases, the replacement of the native Zn2+ with Ni2+ was suggested to lead to higher activity as predicted computationally. There are also intriguing cases, such as Fe2+- and Mn2+-dependent ribonucleotide reductases and W4+- and Mo4+-dependent DMSO reductases, where organisms manage to circumvent the scarcity of one metal (e.g., Fe2+) by creating protein structures that utilize another metal (e.g., Mn2+) for the catalysis of the same reaction. Naturally, even though both metal forms are active, one of the metals is preferred in every-day life, and the other metal variant remains dormant until an emergency strikes in the cell. These examples lead to certain questions. When are catalytic metals selected purely for electronic or structural reasons, implying that enzymatic catalysis is optimized to its maximum? When are metal selections a manifestation of competing evolutionary pressures, where choices are dictated not just by catalytic efficiency but also by other factors in the cell? In other words, how can enzymes be improved as catalysts merely through the use of common biological building blocks available to cells? Addressing these questions is highly relevant to the enzyme design community, where the goal is to prepare maximally efficient quasi-natural enzymes for the catalysis of reactions that interest humankind.Due to competing evolutionary pressures, many natural enzymes may not have evolved to be ideal catalysts and can be improved for the isolated purpose of catalysis in vitro when the competing factors are removed.The goal of this Account is not to cover all the possible stories but rather to highlight how variable enzymatic catalysis can be. We want to bring up possible factors affecting the evolution of enzyme structure, and the large- and intermediate-scale structural and electronic effects that metals can induce in the protein, and most importantly, the opportunities for optimization of these enzymes for catalysis in vitro.

Mixed Pt–Pd clusters deposited on oxides have been of great interest to catalysis. Clusters containing Pt and Pd in roughly equal proportions were found to be unusually stable against sintering, one of the major mechanisms of catalyst deactivation. After aging of such catalysts, the 50/50 Pt–Pd and Pd–O clusters appeared to be the two most prevalent phases. The reason for the enhanced stability of these equally proportioned clusters has remained unclear. In the following, sintering of mixed Pt–Pd clusters on TiO2(110) for various initial atomic concentrations of Pt and Pd and at a range of catalytically relevant temperatures was simulated. It is confirmed that equally mixed clusters have the relatively highest survival rate. Surprisingly, subnanoclusters containing Pt and Pd in all proportions have very similar geometries and chemical bonding, revealing no apparent explanation for favoring the 1:1 Pt/Pd ratio. However, it was discovered that at high temperatures, the 50/50 clusters have considerably more thermally accessible isomers than clusters containing Pt and Pd in other proportions. Hence, one of the reasons for stability is entropic stabilization. Electrostatics also plays a key role as a subtle charge redistribution, and a shift of electron density to the slightly more electronegative Pt results in the partially charged atoms being further stabilized by intracluster Coulomb attraction; this effect is greatest for 1:1 mixtures.Keywords: chemical bonding; density functional theory; Monte Carlo; PtPd clusters on titania; sintering; theory

Pure and doped sub-nanoclusters can exhibit superb catalytic activity, which, however, strongly depends on their size, shape, composition, and the nature of the support. This work is about surface-deposited sub-nano Pt-based clusters, which are promising catalysts for the reactions of dehydrogenation. Using density functional theory and ab initio calculations, and an ab initio genetic algorithm for finding the global minima of clusters, we found a peculiar effect that Pt5 and Pt4Zn clusters exhibit upon deposition on MgO(100). Both of them change shapes from the gas phase 3-D form to a planar form, and they stand upright on the support. Several reasons are responsible for this behaviour. In part, clusters go flat due to the electron transfer from the support. Indeed, the anionic Pt5− and Pt4Zn− species are flat also in the gas phase. Charging induces the second-order Jahn–Teller effect (or partial covalency) facilitated by the recruitment of the higher-energy 6p atomic orbitals on Pt into the valence manifold, and that is the reason for the planarization of the anions. Secondly, clusters maximize interactions with the surface O atoms (resulting in further favouring of 2-D structures over 3-D), and avoid contacts with surface Mg atoms (resulting in upright morphologies).

•Co2+-dependent acireductone dioxygenase exhibits both Fe2+-like and Ni2+-like mechanisms.•Dynamics of reaction may determine the product distribution.•Mixed quantum–classical sampling is required to get the binding of the substrate right.Acireductone dioxygenase (ARD) oxidizes 1,2-dihydroxy-3-keto-5-(methylthio)pentene to either formate and an α-keto acid, or formate, methylthiopropionate and CO, depending on the nature of the catalytic metal, Fe2+ or Ni2+. We recently showed that, contrary to established hypotheses, the mechanistic preference is driven solely by the RedOx behavior of the metal. Here, we address the functionality of Co2+-ARD. Using mixed quantum–classical dynamics simulations and density functional theory calculations, we show that both Fe2+-like and Ni2+-like routes are accessible to Co2+-ARD, but the mechanism involves a bifurcating transition state, and so the exact product distribution would be determined by the reaction dynamics.

We report a joint photoelectron spectroscopic and theoretical study of the PtZnH5– cluster anion. This cluster exhibited an unprecedented planar pentagonal coordination for Pt and an unusual stability and high intensity in the mass spectrum. Both are due to the σ-aromaticity found in the H5-cycle supported by the 5d orbitals on the Pt atom. σ-Aromaticity in all-H systems has been predicted in the past but never found in experimentally observed species. Besides fundamental importance, mixed transition-metal hydrides can be found as intermediates in catalytic processes, and thus, the unexpected stability facilitated by σ-aromaticity can be appreciated also in practical applications.Keywords: cluster hydrides; photoelectron spectroscopy; theory; σ-aromaticity;

The CcrA di-Zn β-lactamase is a bacterial enzyme capable of efficiently hydrolyzing and thus disabling a diverse set of β-lactam antibiotics. Understanding the factors that contribute to the efficiency of CcrA is essential for the design of new CcrA-resistant antibiotics and enzyme inhibitors. The efficacy of CcrA has been speculated to be partially attributable to the flexible protein loop located above the active site (L43-S54), which would mold around structurally different substrates, for snag binding. Confirmation of this hypothesis about the role of the loop has been a challenge, from both an experimental and a theoretical point of view. We employed our newly developed method that combines extensive sampling of the protein structure via discrete molecular dynamics (DMD) and quantum mechanical (QM) treatment of the active site, QM/DMD, to investigate the structural role of the L43-S54 loop in binding three different β-lactam antibiotics: imipenem, ampicillin, and cephalorodine. QM/DMD sampling was followed by high level ab initio calculations for the assessment of the energy contributions to loop-substrate interactions. We show that upon binding of all three antibiotic molecules, the loop comes in direct contact with the substrates and adopts distinctly different conformations depending on the bound substrate. The loop contributes to the binding affinity of CcrA to antibiotics. The primary component of the loop-substrate interaction is hydrophobic, and nonspecific, except for cephalorodine that is capable of π-stacking with W49 via one of the two competing modes.

We show that at the subnano scale, the catalytic properties of surface-supported clusters can be majorly impacted by strategic doping and the choice for the supporting surface. This is a first-principles investigation of CO oxidation catalyzed by two subnanoclusters, Pd4Au and Pd5, deposited on rutile TiO2(110) surfaces. The titania surface was found to participate in the reaction directly via providing additional reaction pathways. The bimetallic cluster Pd4Au shows enhanced catalytic activity, whereas the monometallic Pd5 is poisoned and deactivated in the presence of CO and oxygen, and this trend is reversed from that in the gas phase.Keywords: catalysis; CO oxidation; doping; modeling; surface-supported clusters;

We investigate the physical origin of peptide-induced membrane curvature by contrasting differences between H-bonding interactions of prototypical cationic amino acids, arginine (Arg) and lysine (Lys), with phosphate groups of phospholipid heads using quantum mechanical (QM) calculations of a minimum model and test the results via synthetic oxaorbornene-based transporter sequences without the geometric constraints of polypeptide backbones. QM calculations suggest that although individual Lys can in principle coordinate two phosphates, they are not able to do so at small inter-Lys distances without drastic energetic penalties. In contrast, Arg can coordinate two phosphates down to less than 5 Å, where guanidinium groups can stack “face to face”. In agreement with these observations, poly-Lys cannot generate the nanoscale positive curvature necessary for inducing negative Gaussian membrane curvature, in contrast to poly-Arg. Also consistent with QM calculations, polyguanidine-oxanorbornene homopolymers (PGONs) showed that curvature generation is exquisitely sensitive to the guanidinium group spacing when the phosphate groups are near close packing. Addition of phenyl or butyl hydrophobic groups into guanidine-oxanorbornene polymers increased the amount of induced saddle-splay membrane curvature and broadened the range of lipid compositions where saddle-splay curvature was induced. The enhancement of saddle-splay curvature generation and relaxation of lipid composition requirements via addition of hydrophobicity is consistent with membrane activity profiles. While PGON polymers displayed selective antimicrobial activity against prototypical (Gram positive and negative) bacteria, polymers with phenyl and butyl groups were also active against red blood cells. Our results suggest that it is possible to achieve deterministic molecular design of pore-forming peptides.

CAl42−/− (D4h, 1A1g) is a cluster ion that has been established to be planar, aromatic, and contain a tetracoordinate planar C atom. Valence isoelectronic substitution of C with Si and Ge in this cluster leads to a radical change of structure toward distorted pentagonal species. We find that this structural change goes together with the cluster acquiring partial covalency of bonding between Si/Ge and Al4, facilitated by hybridization of the atomic orbitals (AOs). Counter intuitively, for the AAl42−/− (A = C, Si, Ge) clusters, hybridization in the dopant atom is strengthened from C, to Si, and to Ge, even though typically AOs are more likely to hybridize if they are closer in energy (i.e. in earlier elements in the Periodic Table). The trend is explained by the better overlap of the hybrids of the heavier dopants with the orbitals of Al4. From the thus understood trend, it is inferred that covalency in such clusters can be switched off, by varying the relative sizes of the AOs of the main element and the dopant. Using this mechanism, we then successfully killed covalency in Si, and predicted a new aromatic cluster ion containing a tetracoordinate square planar Si, SiIn42−/−.

We report double σ-aromaticity in a surface-deposited cluster, Pd4, on the TiO2 (110) surface. In the gas phase, Pd4 adopts a tetrahedral structure. However, surface binding promotes a flat, σ-aromatic cluster. This is the first time aromaticity has been found in surface-deposited clusters. The concept of aromaticity is expected to become instrumental in predicting and interpreting properties of such systems, much like it is for isolated molecules and clusters.Keywords: aromaticity; chemical bonding; clusters on surfaces;

Ureases and metallo-β-lactamases are amide hydrolases closely related in function and structure. However, one major difference between them is that the former uses two nickel cations, and the latter uses two zinc cations to do similar catalytic jobs. What is the reason for this choice that Nature made for the catalytic metals? Is it dictated by electronic or structural reasons in the two catalyzed reactions, or some other evolutionary factors? Are both enzymes “perfect” catalysts, as far as just catalysis is concerned, and if they are, then why? Here, we address these questions through a joint quantum mechanical/molecular mechanical dynamics approach and ab initio mechanistic investigation. Five enzyme/substrate systems are considered: urease/urea, CcrA β-lactamase/β-lactam antibiotic model, urease/β-lactam antibiotic model, CcrA β-lactamase/urea, and di-Ni-substituted CcrA β-lactamase/β-lactam antibiotic model. The mechanisms and rates of the metal-facilitated nucleophilic attack are assessed. Both urease and Ni-substituted β-lactamase catalyze the attack on the β-lactam ring with the efficiency surpassing that of natural di-Zn β-lactamase, whereas β-lactamase is unable to hydrolyze urea. These results suggest that in β-lactamases the use of zinc does not provide maximal possible efficiency of the enzyme. Thus, β-lactamases operate by the principle of “good enough”; i.e., the choice for Zn in them leads to a performance that is just satisfactory for its biological purpose but can be evolutionarily improved via replacement of Zn with Ni.

Spontaneous decarboxylation of amino acids is among the slowest known reactions; it is much less facile than the cleavage of amide bonds in polypeptides. Establishment of the kinetics and mechanisms for this fundamental reaction is important for gauging the proficiency of enzymes. In the present study, multiple mechanisms for glycine decomposition in water are explored using QM/MM Monte Carlo simulations and free energy perturbation theory. Simple CO2 detachment emerges as the preferred pathway for decarboxylation; it is followed by water-assisted proton transfer to yield the products: CO2 and methylamine. The computed free energy of activation of 45 kcal/mol, and the resulting rate-constant of 1 × 10–21 s–1, can be compared with an extrapolated experimental rate constant of ∼2 × 10–17 s–1 at 25 °C. The half-life for the reaction is more than 1 billion years. Furthermore, examination of deamination finds simple NH3-detachment yielding α-lactone to be the favored route, though it is less facile than decarboxylation by 6 kcal/mol. Ab initio and DFT calculations with the CPCM hydration model were also carried out for the reactions; the computed free energies of activation for glycine decarboxylation agree with the QM/MM result, whereas deamination is predicted to be more favorable. QM/MM calculations were also performed for decarboxylation of alanine; the computed barrier is 2 kcal/mol higher than for glycine in qualitative accord with experiment.

The chemical bonding being covalent, metallic, or mixed reflects in the structure and properties of solids. How does this play out on the small cluster scale? We report on the interplay between covalent and strongly delocalized bonding in the series of mixed boron–aluminum cluster ions, BnAl6–n2– (n = 0–6), and their lithium salts and show that covalent bonding is an extraordinarily resilient effect that governs the cluster shape more than the delocalized bonding does. The covalent bonding achieved only through the direct B–B interactions is persistent in the considered clusters down to the smallest concentrations of B atoms. As a result, clusters remain planar, and the quality of the delocalized bonding is unavoidably compromised. We explain this trend on the basis of the s–p hybridization of atomic orbitals affordable in the B versus Al atoms. The found effect may be general and not specific to the considered systems.Keywords: chemical bonding; cluster design; clusters; covalency; doping; hybridization; theory;

The human DNA alkyladenine glycosylase (AAG) is a DNA repair enzyme catalyzing the initial step of DNA repair via lesion excision. Its binding site has an incredible plasticity, and recognizes a variety of DNA lesions resulting from deamination or alkylation of adenine. Based on this plasticity, it is natural to wonder how, and if AAG can discriminate against undamaged adenine. It has even been proposed that it cannot. If, however, AAG is specific, the specificity can be expressed at the stage of the base binding, or base excision. There is also a possibility that the propensity of the base to flip out of the DNA double helix governs its selective subsequent removal. Here, we show that binding to AAG is, in fact, dramatically more thermodynamically favorable for hypoxanthine, at least, a specific lesion, produced by oxidative deamination of adenine, than for undamaged adenine. This preference originates from the more constructive interactions of the lesion with the binding site. Of these, a shorter hydrogen bond between the lesion and the backbone of His136 that does not cause a structural distortion of the base in a major player, in agreement with an earlier kinetic study (P.J. O'Brien and T. J. Ellenberger, J. Biol. Chem. 279 (2004), 9750–9757). Mutating His136 to Pro almost completely eliminates the selectivity. Otherwise, bound adenine and the lesion are positioned very similarly at the binding site, suggesting no predisposition to selective removal. The base flip out of the double helix that precedes the binding has approximately equal thermodynamic facility for the lesion and undamaged adenine. This study employs the Monte Carlo simulations in conjunction with Free Energy Perturbation, and Density Functional Theory (DFT) calculations.Research Highlights►Thermodynamics of binding of hypoxanthine lesion to alkyladenine glycosylase is much more favorable than that of undamaged adenine. ►The main reason for this preference is more favorable binding to the active site, majorly due to the hydrogen bond between the lesion and the backbone of His136. ►Thermodynamics of base flipping from the DNA double helix does not favor the lesion over undamaged adenine, however.

A new version of the ab initio gradient embedded genetic algorithm (GEGA) program for finding the global minima on the potential energy surface (PES) of mixed clusters formed by molecules and atoms is reported. The performance of the algorithm is demonstrated on the neutral H·(H2O)n (n = 1−4) clusters, that is, a radical H atom solvated in 1−4 water molecules. These clusters are of a fundamental interest. The solvated hydrogen atom forms during photochemical events in water, or during scavenging of solvated electrons by acids, and transiently exists in biological systems and possibly in inclusion complexes in the deep ocean and in the ice shield of earth. The processes associated with its existence are intriguingly complex, however, and have been the subject of decades-long debates. Using GEGA, we explicate the apparently extreme structural diversity in the H·(H2O)n (n = 1−4) clusters. All considered clusters have four basic structural types: type I, where the H radical is weakly coordinated to the oxygen atom of one of the water molecules; type II, where H is weakly coordinated to a H atom of one of the water molecules; type III, consisting of H2, the OH radical, and n − 1 H2O molecules; and type IV, consisting of H3O and n − 1 H2O. There are myriads of isomers of all four types. The lowest energy species of types I and II are the isoenergetic global minima. H·(H2O)n clusters appear to be a challenging case for GEGA because they have many shallow minima close in energy some of which are significantly less stable than the global minimum. Additionally, the global minima themselves have high structural degeneracy, they are only weakly bound, and they are prone to dissociation. GEGA performed exceptionally well in finding both the global and the low-energy local minima that were subsequently confirmed at higher levels of theory.

•The metal-dependent activity of ARD is explicated computationally.•Contrary to the old hypothesis, Ni and Fe ARD bind acireductone in the same way.•Due to the RedOx flexibility of Fe, Fe ARD stabilizes an additional intermediate.•The existence of this intermediate leads to the formation of different products.Two virtually identical acireductone dioxygenases, ARD and ARD′, catalyze completely different oxidation reactions of the same substrate, 1,2-dihydroxy-3-keto-5-(methylthio)pentene, depending exclusively on the nature of the bound metal. Fe2 +-dependent ARD′ produces the α-keto acid precursor of methionine and formate and allows for the recycling of methionine in cells. Ni2 +-dependent ARD instead produces methylthiopropionate, CO, and formate, and exits the methionine salvage cycle. This mechanistic difference has not been understood to date but has been speculated to be due to the difference in coordination of the substrate to Fe2 + versus Ni2 +: forming a five-membered ring versus a six-membered ring, respectively, thus exposing different carbon atoms for the attack by O2. Here, using mixed quantum-classical molecular dynamics simulations followed by the density functional theory mechanistic investigation, we show that, contrary to the old hypothesis, both metals preferentially bind the substrate as a six-membered ring, exposing the exact same sites to the attack by O2. It is the electronic properties of the metals that are then responsible for the system following different reaction paths, to yield the respective products. We fully explain the puzzling metal-induced difference in functionality between ARD and ARD′ and, in particular, propose a new mechanism for ARD′. All results are in agreement with available isotopic substitution and other experimental data.Download high-res image (101KB)Download full-size image

Quality computational description of metalloproteins is a great challenge due to the vast span of time- and lengthscales characteristic of their existence. We present an efficient new method that allows for robust characterization of metalloproteins. It combines quantum mechanical (QM) description of the metal-containing active site, and extensive dynamics of the protein captured by discrete molecular dynamics (DMD) (QM/DMD). DMD samples the entire protein, including the backbone, and most of the active site, except for the immediate coordination region of the metal. QM operates on the part of the protein of electronic and chemical significance, which may include tens to hundreds of atoms. The breathing quantum-classical boundary provides a continuous mutual feedback between the two machineries. We test QM/DMD using the Fe-containing electron transporter protein, rubredoxin, and its three mutants as a model. QM/DMD can provide a reliable balanced description of metalloproteins’ structure, dynamics, and electronic structure in a reasonable amount of time. As an illustration of QM/DMD capabilities, we then predict the structure of the Ca2+ form of the enzyme catechol O-methyl transferase, which, unlike the native Mg2+ form, is catalytically inactive. The Mg2+ site is ochtahedral, but the Ca2+ is 7-coordinate and features the misalignment of the reacting parts of the system. The change is facilitated by the backbone adjustment. QM/DMD is ideal and fast for providing this level of structural insight.

Computational metalloenzyme design is a multi-scale problem. It requires treating the metal coordination quantum mechanically, extensive sampling of the protein backbone, and additionally accounting for the polarization of the active site by both the metal cation and the surrounding protein (a phenomenon called electrostatic preorganization). We bring together a combination of theoretical methods that jointly offer these desired qualities: QM/DMD for mixed quantum-classical dynamic sampling, quantum theory of atoms in molecules (QTAIM) for the assessment of electrostatic preorganization, and Density Functional Theory (DFT) for mechanistic studies. Within this suite of principally different methods, there are both complementarity of capabilities and cross-validation. Using these methods, predictions can be made regarding the relative activities of related enzymes, as we show on the native Zn2+-dependent carboxypeptidase A (CPA), and its mutant proteins, which are hypothesized to hydrolyze modified substrates. For the native CPA, we replicated the catalytic mechanism and the rate in close agreement with the experiment, giving validity to the QM/DMD predicted structure, the DFT mechanism, and the QTAIM assessment of catalytic activity. For most sequences of the modified substrate and tried CPA mutants, substantially worsened activity is predicted. However, for the substrate mutant that contains Asp instead of Phe at the C-terminus, one CPA mutant exhibits a reasonable activity, as predicted across the theoretical methods. CPA is a well-studied system, and here it serves as a testing ground for the offered methods.

CAl42−/− (D4h, 1A1g) is a cluster ion that has been established to be planar, aromatic, and contain a tetracoordinate planar C atom. Valence isoelectronic substitution of C with Si and Ge in this cluster leads to a radical change of structure toward distorted pentagonal species. We find that this structural change goes together with the cluster acquiring partial covalency of bonding between Si/Ge and Al4, facilitated by hybridization of the atomic orbitals (AOs). Counter intuitively, for the AAl42−/− (A = C, Si, Ge) clusters, hybridization in the dopant atom is strengthened from C, to Si, and to Ge, even though typically AOs are more likely to hybridize if they are closer in energy (i.e. in earlier elements in the Periodic Table). The trend is explained by the better overlap of the hybrids of the heavier dopants with the orbitals of Al4. From the thus understood trend, it is inferred that covalency in such clusters can be switched off, by varying the relative sizes of the AOs of the main element and the dopant. Using this mechanism, we then successfully killed covalency in Si, and predicted a new aromatic cluster ion containing a tetracoordinate square planar Si, SiIn42−/−.

Correction for ‘Pure and Zn-doped Pt clusters go flat and upright on MgO(100)’ by Lu Shen et al., Phys. Chem. Chem. Phys., 2014, 16, 26436–26442.

The mechanism of the formation of coumarins via the Pd-catalyzed intramolecular hydroarylation of the C–C triple bond is elucidated computationally, in corroboration with experimental data. It is shown that the reaction follows the concerted metalation–deprotonation (CMD) mechanism. The typically suspected mechanisms of ambiphilic metal ligand activation (AMLA), electrophilic aromatic substitution (EAS), and oxidative addition (OA) are suggested to be non-competitive, based on predicted conformations and energetics. Two forms of the Pd catalysts are used: Pd(OAc)2, and Pd(TFA)2. The predicted activation free energy barrier for the TFA-based catalyst is lower, both in the gas phase and in the CH2Cl2 solvent, in agreement with the experimental observations. Adding electron-withdrawing groups to the catalyst assists the first and rate-limiting step of the reaction, the deprotonation of the aromatic ring, as understood through charge analysis.

Pure and doped sub-nanoclusters can exhibit superb catalytic activity, which, however, strongly depends on their size, shape, composition, and the nature of the support. This work is about surface-deposited sub-nano Pt-based clusters, which are promising catalysts for the reactions of dehydrogenation. Using density functional theory and ab initio calculations, and an ab initio genetic algorithm for finding the global minima of clusters, we found a peculiar effect that Pt5 and Pt4Zn clusters exhibit upon deposition on MgO(100). Both of them change shapes from the gas phase 3-D form to a planar form, and they stand upright on the support. Several reasons are responsible for this behaviour. In part, clusters go flat due to the electron transfer from the support. Indeed, the anionic Pt5− and Pt4Zn− species are flat also in the gas phase. Charging induces the second-order Jahn–Teller effect (or partial covalency) facilitated by the recruitment of the higher-energy 6p atomic orbitals on Pt into the valence manifold, and that is the reason for the planarization of the anions. Secondly, clusters maximize interactions with the surface O atoms (resulting in further favouring of 2-D structures over 3-D), and avoid contacts with surface Mg atoms (resulting in upright morphologies).

Transition-metal hydrides represent a unique class of compounds, which are essential for catalysis, organic synthesis, and hydrogen storage. In this work we study IrH5(PPh3)2, (RuH5(PiPr3)2)−, (OsH5(PiPr3)2)−, and OsH4(PPhMe2)3 polyhydride complexes, inspired by the recent discovery of the σ-aromatic PtZnH5− cluster anion. The distinctive feature of these molecules is that, like in the PtZnH5− cluster, the metal is five-fold coordinated in-plane, and holds additional ligands at the axial positions. This work shows that the unusual coordination in these compounds indeed can be explained by σ-aromaticity in the pentagonal arrangement, stabilized by the atomic orbitals on the metal. Based on this newly elucidated bonding principle, we additionally propose a new family of polyhydrides that display a uniquely high coordination. We also report the first indications of how aromaticity may impact the reactivity of these molecules.