Measuring Electron Correlation: The Impact of Symmetry and Orbital Transformations.

In this perspective, the various measures of electron correlation used in wave function theory, density functional theory and quantum information theory are briefly reviewed. We then focus on a more traditional metric based on dominant weights in the full configuration solution and discuss its behavior with respect to the choice of the N-electron and the one-electron basis. The impact of symmetry is discussed, and we emphasize that the distinction among determinants, configuration state functions and configurations as reference functions is useful because the latter incorporate spin-coupling into the reference and should thus reduce the complexity of the wave function expansion. The corresponding notions of single determinant, single spin-coupling and single configuration wave functions are discussed and the effect of orbital rotations on the multireference character is reviewed by analyzing a simple model system. In molecular systems, the extent of correlation effects should be limited by finite system size and in most cases the appropriate choices of one-electron and N-electron bases should be able to incorporate these into a low-complexity reference function, often a single configurational one.

Quantum computing in pharma: A multilayer embedding approach for near future applications.

Quantum computers are special purpose machines that are expected to be particularly useful in simulating strongly correlated chemical systems. The quantum computer excels at treating a moderate number of orbitals within an active space in a fully quantum mechanical manner. We present a quantum phase estimation calculation on F2 in a (2,2) active space on Rigetti's Aspen-11 QPU. While this is a promising start, it also underlines the need for carefully selecting the orbital spaces treated by the quantum computer. In this work, a scheme for selecting such an active space automatically is described and simulated results obtained using both the quantum phase estimation (QPE) and variational quantum eigensolver (VQE) algorithms are presented and combined with a subtractive method to enable accurate description of the environment. The active occupied space is selected from orbitals localized on the chemically relevant fragment of the molecule, while the corresponding virtual space is chosen based on the magnitude of interactions with the occupied space calculated from perturbation theory. This protocol is then applied to two chemical systems of pharmaceutical relevance: the enzyme [Fe] hydrogenase and the photosenzitizer temoporfin. While the sizes of the active spaces currently amenable to a quantum computational treatment are not enough to demonstrate quantum advantage, the procedure outlined here is applicable to any active space size, including those that are outside the reach of classical computation.

Perspective on the Current State-of-the-Art of Quantum Computing for Drug Discovery Applications.

Computational chemistry is an essential tool in the pharmaceutical industry. Quantum computing is a fast evolving technology that promises to completely shift the computational capabilities in many areas of chemical research by bringing into reach currently impossible calculations. This perspective illustrates the near-future applicability of quantum computation of molecules to pharmaceutical problems. We briefly summarize and compare the scaling properties of state-of-the-art quantum algorithms and provide novel estimates of the quantum computational cost of simulating progressively larger embedding regions of a pharmaceutically relevant covalent protein-drug complex involving the drug Ibrutinib. Carrying out these calculations requires an error-corrected quantum architecture that we describe. Our estimates showcase that recent developments on quantum phase estimation algorithms have dramatically reduced the quantum resources needed to run fully quantum calculations in active spaces of around 50 orbitals and electrons, from estimated over 1000 years using the Trotterization approach to just a few days with sparse qubitization, painting a picture of fast and exciting progress in this nascent field.

Metal-CO Bonding in Mononuclear Transition Metal Carbonyl Complexes.

DFT calculations have been carried out for coordinatively saturated neutral and charged carbonyl complexes [M(CO) n ] q where M is a metal atom of groups 2-10. The model compounds M(CO)2 (M = Ca, Sr, Ba) and the experimentally observed [Ba(CO)]+ were also studied. The bonding situation has been analyzed with a variety of charge and energy partitioning approaches. It is shown that the Dewar-Chatt-Duncanson model in terms of M ← CO σ-donation and M → CO π-backdonation is a valid approach to explain the M-CO bonds and the trend of the CO stretching frequencies. The carbonyl ligands of the neutral complexes carry a negative charge, and the polarity of the M-CO bonds increases for the less electronegative metals, which is particularly strong for the group 4 and group 2 atoms. The NBO method delivers an unrealistic charge distribution in the carbonyl complexes, while the AIM approach gives physically reasonable partial charges that are consistent with the EDA-NOCV calculations and with the trend of the C-O stretching frequencies. The AdNDP method provides delocalized MOs which are very useful models for the carbonyl complexes. Deep insight into the nature of the metal-CO bonds and quantitative information about the strength of the [M] ← (CO)8 σ-donation and [M(d)] → (CO)8 π-backdonation visualized by the deformation densities are provided by the EDA-NOCV method. The large polarity of the M-CO π orbitals toward the CO end in the alkaline earth octacarbonyls M(CO)8 (M = Ca, Sr, Ba) leads to small values for the delocalization indices δ(M-C) and δ(M···O) and significant overlap between adjacent CO groups, but the origin of the charge migration and the associated red-shift of the C-O stretching frequencies is the [M(d)] → (CO)8 π-backdonation. The heavier alkaline earth metals calcium, strontium and barium use their s/d valence orbitals for covalent bonding. They are therefore to be assigned to the transition metals.

Structure-Guided Rational Design of a Mono- and Diacylglycerol Lipase from Aspergillus oryzae: A Single Residue Mutant Increases the Hydrolysis Ability.

Engineering of enzymes on the basis of protein structures are rational and efficient approaches to acquire biocatalysts of desired performances. In this study, we focused on a special mono- and diacylglycerol lipase (MDGL) isolated from the lipolytic enzyme-enriched fungus Aspergillus oryzae and discovered improved variants based on its crystal structure. We first solved the crystal structure of Aspergillus oryzae lipase (AOL) at 1.7 Å resolution. Structure analysis and sequence alignment of AOL and other MDGLs revealed that the residue V269 is of vital importance for catalysis. Replacement of the V269 in AOL with the corresponding residues in other MDGLs has led to noticeable changes in hydrolysis without sacrificing the thermostability and substrate specificity. Among the investigated variants, V269D exhibited about a six-fold higher hydrolysis activity compared to the wild type. Molecular dynamics simulations and protein-ligand interaction frequency analyses revealed that the Asp substitution enhanced the substrate affinity of AOL. Our work sheds light on understanding the catalytic process of AOL and helps tailoring MDGLs with desired catalytic performance to fulfill the demand for biotechnological applications.

Neutron Scattering Techniques for Studying Metal Complexes in Aqueous Solution.

Neutron scattering combined with ab initio calculations provides a powerful tool for studying metal complexes in different solvents and, particularly, in water. The majority of traditional characterization techniques in catalysis provide only limited information on homogeneous catalytic processes. Neutron scattering, on the other hand, thanks to its sensitivity to hydrogen atoms, and therefore water molecules, can be used to build detailed models of reaction paths and to observe, at a molecular level, the influence of solvent molecules on a catalytic process. In this Mini-Review we describe several examples on how neutron scattering combined with ab initio calculations can be used to examine the nature of the interaction of water molecules with catalytically active metal complexes in solution.

The Valence Orbitals of the Alkaline-Earth Atoms.

Quantum chemical calculations of the alkaline-earth oxides, imides and dihydrides of the alkaline-earth atoms (Ae=Be, Mg, Ca, Sr, Ba) and the calcium cluster Ca6 H9 [N(SiMe3 )2 ]3 (pmdta)3 (pmdta=N,N,N',N'',N''-pentamethyldiethylenetriamine) have been carried out by using density functional theory. Analysis of the electronic structures by charge and energy partitioning methods suggests that the valence orbitals of the lighter atoms Be and Mg are the (n)s and (n)p orbitals. In contrast, the valence orbitals of the heavier atoms Ca, Sr and Ba comprise the (n)s and (n-1)d orbitals. The alkaline-earth metals Be and Mg build covalent bonds like typical main-group elements, whereas Ca, Sr and Ba covalently bind like transition metals. The results not only shed new light on the covalent bonds of the heavier alkaline-earth metals, but are also very important for understanding and designing experimental studies.

d-d Dative Bonding Between Iron and the Alkaline-Earth Metals Calcium, Strontium, and Barium.

Double deprotonation of the diamine 1,1'-(tBuCH2 NH)-ferrocene (1-H2 ) by alkaline-earth (Ae) or EuII metal reagents gave the complexes 1-Ae (Ae=Mg, Ca, Sr, Ba) and 1-Eu. 1-Mg crystallized as a monomer while the heavier complexes crystallized as dimers. The Fe⋅⋅⋅Mg distance in 1-Mg is too long for a bonding interaction, but short Fe⋅⋅⋅Ae distances in 1-Ca, 1-Sr, and 1-Ba clearly support intramolecular Fe⋅⋅⋅Ae bonding. Further evidence for interactions is provided by a tilting of the Cp rings and the related 1 H NMR chemical-shift difference between the Cp α and ß protons. While electrochemical studies are complicated by complex decomposition, UV/Vis spectral features of the complexes support Fe→Ae dative bonding. A comprehensive bonding analysis of all 1-Ae complexes shows that the heavier species 1-Ca, 1-Sr, and 1-Ba possess genuine Fe→Ae bonds which involve vacant d-orbitals of the alkaline-earth atoms and partially filled d-orbitals on Fe. In 1-Mg, a weak Fe→Mg donation into vacant p-orbitals of the Mg atom is observed.

Hepatitis C virus sequence divergence preserves p7 viroporin structural and dynamic features.

The hepatitis C virus (HCV) viroporin p7 oligomerizes to form ion channels, which are required for the assembly and secretion of infectious viruses. The 63-amino acid p7 monomer has two putative transmembrane domains connected by a cytosolic loop, and has both N- and C- termini exposed to the endoplasmic reticulum (ER) lumen. NMR studies have indicated differences between p7 structures of distantly related HCV genotypes. A critical question is whether these differences arise from the high sequence variation between the different isolates and if so, how the divergent structures can support similar biological functions. Here, we present a side-by-side characterization of p7 derived from genotype 1b (isolate J4) in the detergent 6-cyclohexyl-1-hexylphosphocholine (Cyclofos-6) and p7 derived from genotype 5a (isolate EUH1480) in n-dodecylphosphocholine (DPC). The 5a isolate p7 in conditions previously associated with a disputed oligomeric form exhibits secondary structure, dynamics, and solvent accessibility broadly like those of the monomeric 1b isolate p7. The largest differences occur at the start of the second transmembrane domain, which is destabilized in the 5a isolate. The results show a broad consensus among the p7 variants that have been studied under a range of different conditions and indicate that distantly related HCVs preserve key features of structure and dynamics.

Chemical Bonding and Bonding Models of Main-Group Compounds.

The focus of this review is the presentation of the most important aspects of chemical bonding in molecules of the main group atoms according to the current state of knowledge. Special attention is given to the difference between the physical mechanism of covalent bond formation and its description with chemical bonding models, which are often confused. This is partly due to historical reasons, since until the development of quantum theory there was no physical basis for understanding the chemical bond. In the absence of such a basis, chemists developed heuristic models that proved extremely valuable for understanding and predicting experimental studies. The great success of these simple models and the associated rules led to the fact that the model conceptions were regarded as real images of physical reality. The complicated world of quantum theory, which eludes human imagination, made it difficult to link heuristic models of chemical bonding with quantum chemical knowledge. In the early days of quantum chemistry, some suggestions were made which have since proved untenable. In recent decades, there has been a stormy development of quantum chemical methods, which are not limited to the quantitative accuracy of the calculated properties. Also, methods have been developed where the experimentally developed models can be quantitatively expressed and visually represented using mathematically well-defined terms that are derived from quantum chemical calculations. The calculated numbers may however not be measurable values. Nevertheless, as orientation data for the interpretation and classification of experimental findings as well as a guideline for new experiments, they form a coordinate system that defines the multidimensional world of chemistry, which corresponds to the Hilbert space formalism of physics. The nonmeasurability of model values is not a weakness of chemistry but a characteristic by which the infinite complexity of the material world becomes scientifically accessible and very useful for chemical research. This review examines the basis of the commonly used quantum chemical methods for calculating molecules and for analyzing their electronic structure. The bonding situation in selected representative molecules of main-group atoms is discussed. The results are compared with textbook knowledge of common chemistry.

Solvation of Na? in the Sodide Solution, LiNa?10MeNH2.

Alkalides, the alkali metals in their ?1 oxidation state, represent some of the largest and most polarizable atomic species in condensed phases. This study determines the solvation environment around the sodide anion, Na?, in a system of co-solvated Li+. We present isotopically varied total neutron scattering experiments alongside empirical potential structure refinement and ab initio molecular dynamics simulations for the alkali?alkalide system, LiNa?10MeNH2. Both local coordination modes and the intermediate range liquid structure are determined, which demonstrate that distinct structural correlations between cation and anion in the liquid phase extend beyond 8.6 ?. Indeed, the local solvation around Na? is surprisingly well defined with strong solvent orientational order, in contrast to the classical description of alkalide anions not interacting with their environment. The ion-paired Li(MeNH2)4+?Na? species appears to be the dominant alkali?alkalide environment in these liquids, whereby Li+ and Na? share a MeNH2 molecule through the amine group in their primary solvation spheres.

Influence of charge transfer on the isomerisation of stilbene derivatives for application in cancer therapy.

The photoisomerisation of non-toxic trans-combretastatin CA4 to its cytotoxic cis isomer demonstrates the high potential of this and similar compounds for localised cancer therapy. The introduction of intramolecular charge-transfer character by altering the substituents of combretastatin systems opens up possibilities to tailor these stilbene derivatives to the special demands of anticancer drugs. In this TDDFT study we explore how absorption wavelengths for both the trans and cis isomers can be red shifted to enable deeper light penetration into tissue and how the trans → cis and cis → trans isomerisations are affected by charge transfer effects to different degrees.

Anion stabilised hypercloso-hexaalane Al6H6.

Boron hydride clusters are an extremely diverse compound class, which are of enormous importance to many areas of chemistry. Despite this, stable aluminium hydride analogues of these species have remained staunchly elusive to synthetic chemists. Here, we report that reductions of an amidinato-aluminium(III) hydride complex with magnesium(I) dimers lead to unprecedented examples of stable aluminium(I) hydride complexes, [(ArNacnac)Mg]2[Al6H6(Fiso)2] (ArNacnac = [HC(MeCNAr)2]-, Ar = C6H2Me3-2,4,6 Mes; C6H3Et2-2,6 Dep or C6H3Me2-2,6 Xyl; Fiso = [HC(NDip)2]-, Dip = C6H3Pri2-2,6), which crystallographic and computational studies show to possess near neutral, octahedral hypercloso-hexaalane, Al6H6, cluster cores. The electronically delocalised skeletal bonding in these species is compared to that in the classical borane, [B6H6]2-. Thus, the chemistry of classical polyhedral boranes is extended to stable aluminium hydride clusters for the first time.

The hypothiocyanite radical OSCN and its isomers.

A biologically relevant reactive sulfur species (RSS), the hypothiocyanite radical OSCN, is generated in the gas phase through flash vacuum pyrolysis (FVP) of trifluoromethyl sulfinyl cyanide CF3S(O)CN at ca. 1000 K. Upon UV light irradiation (365 nm), OSCN rearranges to novel isomers OSNC and SOCN, and further visible light irradiation (400 ± 20 nm) leads to reverse isomerization. The identification of OSCN, OSNC, and SOCN in cryogenic matrices (Ar and N2, 2.8 K) with IR spectroscopy is supported by quantum chemical calculations up to the CCSD(T)-F12/VTZ-F12 level. The potential energy surface for the interconversion of OSCN isomers and their bonding properties are computationally explored by using the CCSD(T)-F12/VTZ-F12 and EDA-NOCV methods, respectively.

Synthesis, Characterization, and Computational Analysis of the Dialanate Dianion, [H3 Al-AlH3 ]2- : A Valence Isoelectronic Analogue of Ethane.

The first example of a well-defined binary, low-oxidation-state aluminum hydride species that is stable at ambient temperature, namely the dianion in [{(Dep Nacnac)Mg}2 (µ-H)]2 [H3 Al-AlH3 ] (Dep Nacnac=[(DepNCMe)2 CH]- , Dep=2,6-diethylphenyl), has been prepared via a magnesium(I) reduction of the alanate complex, (Dep Nacnac)Mg(µ-H)3 AlH(NEt3 ). An X-ray crystallographic analysis has shown the compound to be a contact ion complex, which computational studies have revealed to be the source of the stability of the aluminum(II) dianion.

Assessing the physiological relevance of alternate architectures of the p7 protein of hepatitis C virus in different environments.

The viroporin p7 of the hepatitis C virus forms multimeric channels eligible for ion transport across the endoplasmic reticulum membrane. Currently the subject of many studies and discussion, the molecular assembly of the ion channel and the structural characteristics of the p7 monomer are not yet fully understood. Structural investigation of p7 has been carried out only in detergent environments, making the interpretation of the experimental results somewhat questionable. Here, we analyze by means of molecular dynamics simulations the structure of the p7 monomer as a function of its sequence, initial conformation and environment. We investigate the conductance properties of three models of a hexameric p7 ion channel by examining ion translocation in a pure lipid bilayer. It is noteworthy that although none of the models reflects the experimentally observed trend to conduct preferentially cations, we were able to identify the position and orientation of titratable acidic or basic residues playing a crucial role in ion selectivity and in the overall conductance of the channel. In addition, too compact a packing of the monomers leads to channel collapse rather than formation of a reasonable pore, amenable to ion translocation. The present findings are envisioned to help assess the physiological relevance of p7 ion channel models consisting of multimeric structures obtained in non-native environments.

Donor-acceptor bonding in novel low-coordinated compounds of boron and group-14 atoms C-Sn.

A summary of theoretical and experimental work in the area of low-coordinated compounds of boron and group-14 atoms C-Sn in the last decade is presented. The focus of the account lies on molecules EL2, E2L2 and E3L3, which possess dative bonds between one, two or three atoms E and σ-donor ligands L that stabilize the atoms E through L→E donor-acceptor interactions. The interplay between theory and experiment provides detailed insight into the bonding situation of the molecules, which serves as guideline for the synthesis of molecules that possess unusual bonding motifs.

The fate of NHC-stabilized dicarbon.

The attempted synthesis of NHC-stabilized dicarbon (NHC=C=C=NHC) through deprotonation of a doubly protonated precursor ([NHC-CH=CH-NHC](2+) ) is reported. Rather than deprotonation, a clean reduction to NHC=CH-CH=NHC is observed with a variety of bases. The apparent resistance towards deprotonation to the target compound led to a reinvestigation of the electronic structure of NHC→CC←NHC, which showed that the highest occupied molecular orbital/lowest unoccupied molecular orbital (HOMO/LUMO) gap is likely too small to allow for isolation of this species. This is in contrast to the recent isolation of the cyclic alkylaminocarbene analogue (cAAC=C=C=cAAC), which has a large HOMO-LUMO gap. A detailed theoretical study illuminates the differences in electronic structures between these molecules, highlighting another case of the potential advantages of using cAAC rather than NHC as a ligand. The bonding analysis suggests that the dicarbon compounds are well represented in terms of donor-acceptor interactions L→C2 ←L (L=NHC, cAAC).

Direct estimate of the internal π-donation to the carbene centre within N-heterocyclic carbenes and related molecules.

Fifteen cyclic and acylic carbenes have been calculated with density functional theory at the BP86/def2-TZVPP level. The strength of the internal X→p(π) π-donation of heteroatoms and carbon which are bonded to the C(II) atom is estimated with the help of NBO calculations and with an energy decomposition analysis. The investigated molecules include N-heterocyclic carbenes (NHCs), the cyclic alkyl(amino)carbene (cAAC), mesoionic carbenes and ylide-stabilized carbenes. The bonding analysis suggests that the carbene centre in cAAC and in diamidocarbene have the weakest X→p(π) π-donation while mesoionic carbenes possess the strongest π-donation.