Simulating X-ray Absorption Spectroscopy in Challenging Environments: Methodological Insights from Water-Solvated Ammonia and Ammonium Systems.

Core-electron excitations in solvated systems, influenced by solvent geometry and hydrogen bonding, make X-ray absorption spectroscopy (XAS) a valuable tool for assessing solvent-solute interactions. However, calculating XAS spectra with electronic-structure methods has proven challenging due to a delicate interplay between correlation and solvation effects. This study provides a computational procedure for XAS modeling in solvated systems, with water-solvated ammonia and ammonium systems serving as probes. Exploring methodological challenges, we investigate explicit embedding models, specifically the polarizable embedding family, including polarizable density embedding and extended polarizable density embedding. Our linear-response time-dependent density functional theory (LR-TDDFT) XAS calculations reveal the efficiency of this approach, with extended polarizable density embedding emerging as a robust improvement over polarizable density embedding. Contrary to some recent literature, our study challenges the belief that LR-TDDFT cannot accurately describe XAS spectra of ammonia and ammonium solvated in water.

A frontier-orbital view of the initial steps of lytic polysaccharide monooxygenase reactions.

Lytic polysaccharide monooxygenases (LPMOs) are copper enzymes that oxidatively cleave the strong C-H bonds in recalcitrant polysaccharide substrates, thereby playing a crucial role in biomass degradation. Recently, LPMOs have also been shown to be important for several pathogens. It is well established that the Cu(II) resting state of LPMOs is inactive, and the electronic structure of the active site needs to be altered to transform the enzyme into an active form. Whether this transformation occurs due to substrate binding or due to a unique priming reduction has remained speculative. Starting from four different crystal structures of the LPMO LsAA9A with well-defined oxidation states, we use a frontier molecular orbital approach to elucidate the initial steps of the LPMO reaction. We give an explanation for the requirement of the unique priming reduction and analyse electronic structure changes upon substrate binding. We further investigate how the presence of the substrate could facilitate an electron transfer from the copper active site to an H2O2 co-substrate. Our findings could help to control experimental LPMO reactions.

Accuracy of One- and Two-Photon Intensities with the Extended Polarizable Density Embedding Model.

The recently developed extended polarizable density embedding (PDE-X) model is evaluated for the spectroscopic properties of organic chromophores solvated in water, including both one- and two-photon absorption properties. The PDE-X embedding model systematically improves vertical excitation energies over the preceding polarizable density embedding model (PDE). PDE-X shows more modest improvements over existing embedding models for oscillator strengths and two-photon absorption cross-sections, which are more sensitive properties. We argue that the origin of these discrepancies is related to the description of polarization effects, suggesting directions for future development of the embedding model.

Histidine oxidation in lytic polysaccharide monooxygenase.

The lytic polysaccharide monooxygenases (LPMOs) comprise a super-family of copper enzymes that boost the depolymerisation of polysaccharides by oxidatively disrupting the glycosidic bonds connecting the sugar units. Industrial use of LPMOs for cellulose depolymerisation has already begun but is still far from reaching its full potential. One issue is that the LPMOs self-oxidise and thereby deactivate. The mechanism of this self-oxidation is unknown, but histidine residues coordinating to the copper atom are the most susceptible. An unusual methyl modification of the NE2 atom in one of the coordinating histidine residues has been proposed to have a protective role. Furthermore, substrate binding is also known to reduce oxidative damage. We here for the first time investigate the mechanism of histidine oxidation with combined quantum and molecular mechanical (QM/MM) calculations, with outset in intermediates previously shown to form from a reaction with peroxide and a reduced LPMO. We show that an intermediate with a [Cu-O]+ moiety is sufficiently potent to oxidise the nearest C-H bond on both histidine residues, but methylation of the NE2 atom of His-1 increases the reaction barrier of this reaction. The substrate further increases the activation barrier. We also investigate a [Cu-OH]2+ intermediate with a deprotonated tyrosine radical. This intermediate was previously proposed to have a protective role, and we also find it to have higher barriers than the corresponding a [Cu-O]+ intermediate.

A method to capture the large relativistic and solvent effects on the UV-vis spectra of photo-activated metal complexes.

We have recently developed a method based on relativistic time-dependent density functional theory (TD-DFT) that allows the calculation of electronic spectra in solution (Creutzberg, Hedegård, J. Chem. Theory Comput.18, 2022, 3671). This method treats the solvent explicitly with a classical, polarizable embedding (PE) description. Furthermore, it employs the complex polarization propagator (CPP) formalism which allows calculations on complexes with a dense population of electronic states (such complexes are known to be problematic for conventional TD-DFT). Here, we employ this method to investigate both the dynamic and electronic effects of the solvent for the excited electronic states of trans-trans-trans-[Pt(N3)2(OH)2(NH3)2] in aqueous solution. This complex decomposes into species harmful to cancer cells under light irradiation. Thus, understanding its photo-physical properties may lead to a more efficient method to battle cancer. We quantify the effect of the underlying structure and dynamics by classical molecular mechanics simulations, refined with a subsequent DFT or semi-empirical optimization on a cluster. Moreover, we quantify the effect of employing different methods to set up the solvated system, e.g., how sensitive the results are to the method used for the refinement, and how large a solvent shell that is required. The electronic solvent effect is always included through a PE potential.

Multiconfigurational short-range density functional theory for nuclear magnetic resonance shielding constants with gauge-including atomic orbitals.

In this paper, we present the theory and implementation of nuclear magnetic resonance shielding constants with gauge-including atomic orbitals for the hybrid multiconfigurational short-range density functional theory model. As a special case, this implementation also includes Hartree-Fock srDFT (HF-srDFT). Choosing a complete-active space (CAS) wave function as the multiconfigurational parameterization of the wave function, we investigate how well CAS-srDFT reproduces experimental trends of nuclear shielding constants compared to DFT and complete active space self-consistent field (CASSCF). Calculations on the nucleobases adenine and thymine show that CAS-srDFT performs on average the best of the tested methods, much better than CASSCF but only marginally better than HF-srDFT. The performance, compared to regular DFT, is similar when functionals containing exact exchange are used. We generally find that the inclusion of exact exchange is important for an accurate description of the shielding constants. In cases where no exact exchange is included, we observe that the HF- and CAS-srDFT often outperform regular DFT. For calculations on transition metal nuclei in organometallic compounds with significant static correlation, the CAS-srDFT method again outperforms CASSCF compared to experimental shielding constants, and the change from HF-srDFT is substantial. In conclusion, the static correlation posed by the metal complexes seems to be captured by CAS-srDFT, which is promising since this type of correlation is not well described by regular DFT.

Nuclear Magnetic Shielding Constants with the Polarizable Density Embedding Model.

We extend the polarizable density embedding (PDE) model to support the calculation of nuclear magnetic resonance (NMR) shielding constants using gauge-including atomic orbitals (GIAOs) within a density functional theory (DFT) framework. The PDE model divides the total system into fragments, describing some by quantum mechanics (QM) and the others through an embedding model. The PDE model uses anisotropic polarizabilities, inter-fragment two-electron Coulomb integrals, and a non-local repulsion operator to emulate the QM effects. The terms involving Coulomb integrals are straightforwardly extended with GIAOs. In contrast, we consider two approaches to handle the gauge dependency of the non-local operator, employing either simple symmetrization or a gauge transformation. We find the latter approach to be most stable with respect to increasing the basis set size of the QM region. We examine the accuracy of the PDE model for calculating NMR shielding constants on several solutes in a water solution. The performance is compared with the classical polarizable embedding (PE) model in addition to supermolecular reference calculations. Based on these systems, we address the basis set convergence characteristics and the QM region size requirements. Furthermore, we investigate the performance of the PDE model for a system with significant electron spill-out. In many cases, we find that the PDE model outperforms the PE model, especially regarding the accuracy of nuclear shielding constants when using small QM region sizes and in systems with significant electron spill-out.

New relativistic quantum chemical methods for understanding light-induced therapeutics.

The inorganic platinum complexes currently in clinical use for cancer treatment have severe side effects, and complexes with fewer side effects are required. One option is to use complexes that are inactive until they are light-activated. Theoretical chemistry can contribute to the design of these complexes, but most current theoretical methods lack explicit treatment of relativistic effects (since the target complexes often contain heavy elements). In particular, spin-orbit coupling is required for accurate predictions of the complexes' photo-physical properties. In this perspective, we summarize relativistic methods developed in recent years that can contribute to our understanding of light-induced reactivity and thereby help predict new, suitable complexes.

Fragmentation-Based Decomposition of a Metalloenzyme-Substrate Interaction: A Case Study for a Lytic Polysaccharide Monooxygenase.

We present a novel decomposition scheme for electronic interaction energies based on the flexible formulation of fragmentation schemes through fragment combination ranges (FCRs; J. Chem. Phys., 2021, 155, 164105). We devise a clear additive decomposition with contribution of nondisjoint fragments and correction terms for overlapping fragments and apply this scheme to the metalloenzyme-substrate complex of a lytic polysaccharide monooxygenase (LPMO) with an oligosaccharide. By this, we further illustrate the straightforward adaptability of the FCR-based schemes to novel systems. Our calculations suggest that the description of the electronic structure is a larger error source than the fragmentation scheme. In particular, we find a large impact of the basis set size on the interaction energies. Still, the introduction of three-body interaction terms in the fragmentation setup improves the agreement to the supermolecular reference. Yet, the qualitative results for the decomposition scheme with two-body terms only largely agree within the investigated electronic-structure approaches and basis sets, which are B97-3c, DFT (TPSS and B3LYP), and MP2 methods. The overlap contributions are found to be small, allowing analysis of the interaction energy into individual amino acid residues: We find a particularly strong interaction between the substrate and the LPMO copper active site.

Cooperative Co-Activation of Water and Hypochlorite by a Non-Heme Diiron(III) Complex.

Aqueous solutions of the iron(III) complex of N,N,N'-tris(2-pyridylmethyl)ethylenediamine-N'-acetate (tpena) react with hypochlorite (ClO-) to produce the reactive high-valent [FeIV(O)(tpena)]+. Under catalytic conditions, in bicarbonate-buffered media (pH 8) with a set ionic strength (10 mM NaCl), kinetic analysis shows that two equivalents of [FeIV(O)(tpena)]+ per one ClO- are produced, with benign chloride ions the only byproduct. An unprecedented supramolecular activation of ClO- by {(HCO3)⊂[(tpena)FeIII(µ-O)FeIII(Htpena)]}2+ is proposed. This mode of activation has great advantage for use in the catalytic oxidation of C-H bonds in water since: (i) the catalyst scaffold is protected from oxidative degradation and (ii) undesirable radical side reactions which produce toxic chlorinated compounds are circumvented by this novel coactivation of water and ClO-. The unique activation mechanism by the Fe-tpena system makes possible the destruction of organic contaminants as an add-on technology to water disinfection by chlorination, demonstrated here through (i) the catalytic oxidation of micropollutant metaldehyde, and (ii) mineralization of the model substrate formate. The resting-state speciation at pH 3, 5, 7, and 9, as well as the catalytically active iron speciation are characterized with Mössbauer and EPR spectroscopy and supported by DFT calculations. Our study provides fundamentally new insights into the design and activation mode of iron-based catalysts relevant to applications in water remediation.

Investigating the influence of relativistic effects on absorption spectra for platinum complexes with light-activated activity against cancer cells.

We report the first systematic investigation of relativistic effects on the UV-vis spectra of two prototype complexes for so-called photo-activated chemotherapy (PACT), trans-trans-trans-[Pt(N3)2(OH)2(NH3)2] and cis-trans-cis-[Pt(N3)2(OH)2(NH3)2]. In PACT, design of new drugs requires in-depth understanding of the photo-activation mechanisms. A first step is usually to rationalize their UV-vis spectra for which time-dependent density functional theory (TD-DFT) is an indispensable tool. We carried out TD-DFT calculations with a systematic series of non-relativistic (NR), scalar-relativistic (SR), and four-component (4c) Hamiltonians. As expected, large differences are found between spectra calculated within 4c and NR frameworks, while the most intense features (found at higher energies below 300 nm) can be reasonably well reproduced within a SR framework. It is also shown that effective core potentials (ECPs) yield essentially similar results as all-electron SR calculations. Yet the underlying transitions can be strongly influenced by spin-orbit coupling, which is only present in the 4c framework: while this can affect both intense and less intense transitions in the spectra, the effect is most pronounced for weaker transitions at lower energies, above 300 nm. Since the investigated complexes are activated with light of wavelengths above 300 nm, employing a method with explicit inclusion of spin-orbit coupling may be crucial to rationalize the activation mechanism.

The DIRAC code for relativistic molecular calculations.

DIRAC is a freely distributed general-purpose program system for one-, two-, and four-component relativistic molecular calculations at the level of Hartree-Fock, Kohn-Sham (including range-separated theory), multiconfigurational self-consistent-field, multireference configuration interaction, electron propagator, and various flavors of coupled cluster theory. At the self-consistent-field level, a highly original scheme, based on quaternion algebra, is implemented for the treatment of both spatial and time reversal symmetry. DIRAC features a very general module for the calculation of molecular properties that to a large extent may be defined by the user and further analyzed through a powerful visualization module. It allows for the inclusion of environmental effects through three different classes of increasingly sophisticated embedding approaches: the implicit solvation polarizable continuum model, the explicit polarizable embedding model, and the frozen density embedding model.

Triplet excitation energies from multiconfigurational short-range density-functional theory response calculations.

Linear response theory for the multiconfigurational short-range density functional theory (MC-srDFT) model is extended to triplet response with a singlet reference wave function. The triplet linear response equations for MC-srDFT are derived for a general hybrid srGGA functional and implemented in the Dalton program. Triplet excitation energies are benchmarked against the CC3 model of coupled cluster theory and the complete-active-space second-order perturbation theory using three different short-range functionals (srLDA, srPBE, and srPBE0), both with full linear response and employing the generalized Tamm-Dancoff approximation (gTDA). We find that using gTDA is required for obtaining reliable triplet excitations; for the CAS-srPBE model, the mean absolute deviation decreases from 0.40 eV to 0.26 eV, and for the CAS-srLDA model, it decreases from 0.29 eV to 0.21 eV. As expected, the CAS-srDFT model is found to be superior to the HF-srDFT model when analyzing the calculated triplet excitations for molecules in the benchmark set where increased static correlation is expected.

Multiconfigurational short-range density-functional theory for open-shell systems.

Many chemical systems cannot be described by quantum chemistry methods based on a single-reference wave function. Accurate predictions of energetic and spectroscopic properties require a delicate balance between describing the most important configurations (static correlation) and obtaining dynamical correlation efficiently. The former is most naturally done through a multiconfigurational (MC) wave function, whereas the latter can be done by, e.g., perturbation theory. We have employed a different strategy, namely, a hybrid between multiconfigurational wave functions and density-functional theory (DFT) based on range separation. The method is denoted by MC short-range DFT (MC-srDFT) and is more efficient than perturbative approaches as it capitalizes on the efficient treatment of the (short-range) dynamical correlation by DFT approximations. In turn, the method also improves DFT with standard approximations through the ability of multiconfigurational wave functions to recover large parts of the static correlation. Until now, our implementation was restricted to closed-shell systems, and to lift this restriction, we present here the generalization of MC-srDFT to open-shell cases. The additional terms required to treat open-shell systems are derived and implemented in the DALTON program. This new method for open-shell systems is illustrated on dioxygen and [Fe(H2O)6]3+.

Molecular mechanism of lytic polysaccharide monooxygenases.

The lytic polysaccharide monooxygenases (LPMOs) are copper metalloenzymes that can enhance polysaccharide depolymerization through an oxidative mechanism and hence boost generation of biofuel from e.g. cellulose. By employing density functional theory in a combination of quantum mechanics and molecular mechanics (QM/MM), we report a complete description of the molecular mechanism of LPMOs. The QM/MM scheme allows us to describe all reaction steps with a detailed protein environment and we show that this is necessary. Several active species capable of abstracting a hydrogen from the substrate have been proposed previously and starting from recent crystallographic work on a substrate-LPMO complex, we investigate previously suggested paths as well as new ones. We describe the generation of the reactive intermediates, the abstraction of a hydrogen atom from the polysaccharide substrate, as well as the final recombination step in which OH is transferred back to the substrate. We show that a superoxo [CuO2]+ complex can be protonated by a nearby histidine residue (suggested by recent mutagenesis studies and crystallographic work) and, provided an electron source is available, leads to formation of an oxyl-complex after cleavage of the O-O bond and dissociation of water. The oxyl complex either reacts with the substrate or is further protonated to a hydroxyl complex. Both the oxyl and hydroxyl complexes are also readily generated from a reaction with H2O2, which was recently suggested to be the true co-substrate, rather than O2. The C-H abstraction by the oxyl and hydroxy complexes is overall favorable with activation barriers of 69 and 94 kJ mol-1, compared to the much higher barrier (156 kJ mol-1) obtained for the copper-superoxo species. We obtain good structural agreement for intermediates for which structural data are available and the estimated reaction energies agree with experimental rate constants. Thus, our suggested mechanism is the most complete to date and concur with available experimental evidence.

Modeling the absorption spectrum of the permanganate ion in vacuum and in aqueous solution.

The absorption spectrum of the MnO4- ion has been a test-bed for quantum-chemical methods over the last decades. Its correct description requires highly-correlated multiconfigurational methods, which are incompatible with the inclusion of finite-temperature and solvent effects due to their high computational demands. Therefore, implicit solvent models are usually employed. Here we show that implicit solvent models are not sufficiently accurate to model the solvent shift of MnO4-, and we analyze the origins of their failure. We obtain the correct solvent shift for MnO4- in aqueous solution by employing the polarizable embedding (PE) model combined with a range-separated complete active space short-range density functional theory method (CAS-srDFT). Finite-temperature effects are taken into account by averaging over structures obtained from ab initio molecular dynamics simulations. The explicit treatment of finite-temperature and solvent effects facilitates the interpretation of the bands in the low-energy region of the MnO4- absorption spectrum, whose assignment has been elusive.

Relativistic Polarizable Embedding.

Most chemistry, including chemistry where relativistic effects are important, occurs in an environment, and in many cases, this environment has a significant effect on the chemistry. In nonrelativistic quantum chemistry, a lot of progress has been achieved with respect to including environments such as a solvent or protein in the calculations, and now is the time to extend the possibilities for also doing this in relativistic quantum chemistry. The polarizable embedding (PE) model efficiently incorporates electrostatic effects of the environment by describing it as a collection of localized electric multipoles and polarizabilities obtained through quantum chemical calculations. In this article, we present the theory and implementation of four- and exact two-component Hamiltonians within a PE framework. We denote the methods the PE-4c-DFT and PE-X2C-DFT models. The models include a linear response formalism to calculate time-dependent (TD) properties: PE-TD-4c-DFT and PE-TD-X2C-DFT. With this first implementation, we calculate the PE-TD-4c-PBE0 excitation energies of the TcO4- and ReO4- ions in an explicit water solvent. This initial investigation focuses on the relative size of relativistic and solvent contributions to the excitation energies. The solvent effect is divided into an indirect solvent effect due to the structural perturbation of the XO4- ion and a direct electrostatic effect. The relativistic effects as well as both types of solvent effects are found to contribute to a shift in the excitation energies, but they do so to different extents depending on the ion and the electronic transition in question.

New Approaches for ab initio Calculations of Molecules with Strong Electron Correlation.

Reliable quantum chemical methods for the description of molecules with dense-lying frontier orbitals are needed in the context of many chemical compounds and reactions. Here, we review developments that led to our new computational toolbox which implements the quantum chemical density matrix renormalization group in a second-generation algorithm. We present an overview of the different components of this toolbox.

Density matrix renormalization group with efficient dynamical electron correlation through range separation.

We present a new hybrid multiconfigurational method based on the concept of range-separation that combines the density matrix renormalization group approach with density functional theory. This new method is designed for the simultaneous description of dynamical and static electron-correlation effects in multiconfigurational electronic structure problems.

Multiscale modeling of the active site of [Fe] hydrogenase: the H2 binding site in open and closed protein conformations.

A series of QM/MM optimizations of the full protein of [Fe] hydrogenase were performed. The FeGP cofactor has been optimized in the water-bound resting state (1), with a side-on bound dihydrogen (2), or as a hydride intermediate (3). For inclusion of H4MPT in the closed structure, advanced multiscale modeling appears to be necessary, especially to obtain reliable distances between CH-H4MPT(+) and the dihydrogen (H2) or hydride (H(-)) ligand in the FeGP cofactor. Inclusion of the full protein is further important for the relative energies of the two intermediates 2 and 3. We finally find that hydride transfer from 3 has a significantly higher barrier than found in previous studies neglecting the full protein environment.