Eliminating Imaginary Vibrational Frequencies in Quantum-Chemical Cluster Models of Enzymatic Active Sites.

In constructing finite models of enzyme active sites for quantum-chemical calculations, atoms at the periphery of the model must be constrained to prevent unphysical rearrangements during geometry relaxation. A simple fixed-atom or "coordinate-lock" approach is commonly employed but leads to undesirable artifacts in the form of small imaginary frequencies. These preclude evaluation of finite-temperature free-energy corrections, limiting thermochemical calculations to enthalpies only. Full-dimensional vibrational frequency calculations are possible by replacing the fixed-atom constraints with harmonic confining potentials. Here, we compare that approach to an alternative strategy in which fixed-atom contributions to the Hessian are simply omitted. While the latter strategy does eliminate imaginary frequencies, it tends to underestimate both the zero-point energy and the vibrational entropy while introducing artificial rigidity. Harmonic confining potentials eliminate imaginary frequencies and provide a flexible means to construct active-site models that can be used in unconstrained geometry relaxations, affording better convergence of reaction energies and barrier heights with respect to the model size, as compared to models with fixed-atom constraints.

Water-Mediated Charge Transfer and Electron Localization in a Co3Fe2 Cyanide-Bridged Trigonal Bipyramidal Complex.

The effects of temperature and chemical environment on a pentanuclear cyanide-bridged, trigonal bipyramidal molecular paramagnet have been investigated. Using element- and oxidation state-specific near-ambient pressure X-ray photoemission spectroscopy (NAP-XPS) to probe charge transfer and second order, nonlinear vibrational spectroscopy, which is sensitive to symmetry changes based on charge (de)localization coupled with DFT, a detailed picture of environmental effects on charge-transfer-induced spin transitions is presented. The molecular cluster, Co3Fe2(tmphen)6(µ-CN)6(t-CN)6, abbrev. Co3Fe2, shows changes in electronic behavior depending on the chemical environment. NAP-XPS shows that temperature changes induce a metal-to-metal charge transfer (MMCT) in Co3Fe2 between a Co and Fe center, while cycling between ultrahigh vacuum and 2 mbar of water at constant temperature causes oxidation state changes not fully captured by the MMCT picture. Sum frequency generation vibrational spectroscopy (SFG-VS) probes the role of the cyanide ligand, which controls the electron (de)localization via the superexchange coupling. Spectral shifts and intensity changes indicate a change from a charge delocalized, Robin-Day class II/III high spin state to a charge-localized, class I low spin state consistent with DFT. In the presence of a H-bonding solvent, the complex adopts a localized electronic structure, while removal of the solvent delocalizes the charges and drives an MMCT. This change in Robin-Day classification of the complex as a function of chemical environment results in reversible switching of the dipole moment, analogous to molecular multiferroics. These results illustrate the important role of the chemical environment and solvation on underlying charge and spin transitions in this and related complexes.

Visualizing and characterizing excited states from time-dependent density functional theory.

Time-dependent density functional theory (TD-DFT) is the most widely-used electronic structure method for excited states, due to a favorable combination of low cost and semi-quantitative accuracy in many contexts, even if there are well recognized limitations. This Perspective describes various ways in which excited states from TD-DFT calculations can be visualized and analyzed, both qualitatively and quantitatively. This includes not just orbitals and densities but also well-defined statistical measures of electron-hole separation and of Frenkel-type exciton delocalization. Emphasis is placed on mathematical connections between methods that have often been discussed separately. Particular attention is paid to charge-transfer diagnostics, which provide indicators of when TD-DFT may not be trustworthy due to its categorical failure to describe long-range electron transfer. Measures of exciton size and charge separation that are directly connected to the underlying transition density are recommended over more ad hoc metrics for quantifying charge-transfer character.

Spectroscopy and dynamics of the hydrated electron at the water/air interface.

The hydrated electron, e-(aq), has attracted much attention as a central species in radiation chemistry. However, much less is known about e-(aq) at the water/air surface, despite its fundamental role in electron transfer processes at interfaces. Using time-resolved electronic sum-frequency generation spectroscopy, the electronic spectrum of e-(aq) at the water/air interface and its dynamics are measured here, following photo-oxidation of the phenoxide anion. The spectral maximum agrees with that for bulk e-(aq) and shows that the orbital density resides predominantly within the aqueous phase, in agreement with supporting calculations. In contrast, the chemistry of the interfacial hydrated electron differs from that in bulk water, with e-(aq) diffusing into the bulk and leaving the phenoxyl radical at the surface. Our work resolves long-standing questions about e-(aq) at the water/air interface and highlights its potential role in chemistry at the ubiquitous aqueous interface.

Ground-State Orbital Analysis Predicts S1 Charge Transfer in Donor-Acceptor Materials.

Donor-acceptor (D-A) materials can exhibit a wide range of unique photophysical properties with applications in next-generation optoelectronics. Electronic structure calculations of D-A dimers are often employed to predict the properties of D-A materials. One of the most important D-A dimer quantities is the degree of charge transfer (DCT) in the S1 state, which correlates with properties such as fluorescence lifetimes and intersystem crossing rates in D-A materials. While predictive metrics of the S1 DCT generally require an excited-state quantum chemistry calculation, presented here is a novel metric that predicts S1 DCT solely with ground-state orbital analysis. This metric quantifies the similarity of the orbitals between a dimer complex and its monomer components. A linear relationship is found between this similarity metric and the S1 DCT, calculated using a data set of 31 D-A dimers. Best practices for integrating this novel orbital structure-function relationship into high-throughput screening methods are discussed.

Scalable generalized screening for high-order terms in the many-body expansion: Algorithm, open-source implementation, and demonstration.

The many-body expansion lies at the heart of numerous fragment-based methods that are intended to sidestep the nonlinear scaling of ab initio quantum chemistry, making electronic structure calculations feasible in large systems. In principle, inclusion of higher-order n-body terms ought to improve the accuracy in a controllable way, but unfavorable combinatorics often defeats this in practice and applications with n ≥ 4 are rare. Here, we outline an algorithm to overcome this combinatorial bottleneck, based on a bottom-up approach to energy-based screening. This is implemented within a new open-source software application ("Fragme∩t"), which is integrated with a lightweight semi-empirical method that is used to cull subsystems, attenuating the combinatorial growth of higher-order terms in the graph that is used to manage the calculations. This facilitates applications of unprecedented size, and we report four-body calculations in (H2O)64 clusters that afford relative energies within 0.1 kcal/mol/monomer of the supersystem result using less than 10% of the unique subsystems. We also report n-body calculations in (H2O)20 clusters up to n = 8, at which point the expansion terminates naturally due to screening. These are the largest n-body calculations reported to date using ab initio electronic structure theory, and they confirm that high-order n-body terms are mostly artifacts of basis-set superposition error.

Time-Dependent Density Functional Theory for X-ray Absorption Spectra: Comparing the Real-Time Approach to Linear Response.

We simulate X-ray absorption spectra at elemental K-edges using time-dependent density functional theory (TDDFT) in both its conventional linear-response implementation and its explicitly time-dependent or "real-time" formulation. Real-time TDDFT simulations enable broadband spectra calculations without the need to invoke frozen occupied orbitals ("core/valence separation"), but we find that these spectra are often contaminated by transitions to the continuum that originate from lower-energy core and semicore orbitals. This problem becomes acute in triple-ζ basis sets, although it is sometimes sidestepped in double-ζ basis sets. Transitions to the continuum acquire surprisingly large dipole oscillator strengths, leading to spectra that are difficult to interpret. Meaningful spectra can be recovered by means of a filtering technique that decomposes the spectrum into contributions from individual occupied orbitals, and the same procedure can be used to separate L- and K-edge spectra arising from different elements within a given molecule. In contrast, conventional linear-response TDDFT requires core/valence separation but is free of these artifacts. It is also significantly more efficient than the real-time approach, even when hundreds of individual states are needed to reproduce near-edge absorption features and even when Padé approximants are used to reduce the real-time simulations to just 2-4 fs of time propagation. Despite the cost, the real-time approach may be useful to examine the validity of the core/valence separation approximation.

Fractional-Electron and Transition-Potential Methods for Core-to-Valence Excitation Energies Using Density Functional Theory.

Methods for computing X-ray absorption spectra based on a constrained core hole (possibly containing a fractional electron) are examined. These methods are based on Slater's transition concept and its generalizations, wherein core-to-valence excitation energies are determined using Kohn-Sham orbital energies. Methods examined here avoid promoting electrons beyond the lowest unoccupied molecular orbital, facilitating robust convergence. Variants of these ideas are systematically tested, revealing a best-case accuracy of 0.3-0.4 eV (with respect to experiment) for K-edge transition energies. Absolute errors are much larger for higher-lying near-edge transitions but can be reduced below 1 eV by introducing an empirical shift based on a charge-neutral transition-potential method, in conjunction with functionals such as SCAN, SCAN0, or B3LYP. This procedure affords an entire excitation spectrum from a single fractional-electron calculation, at the cost of ground-state density functional theory and without the need for state-by-state calculations. This shifted transition-potential approach may be especially useful for simulating transient spectroscopies or in complex systems where excited-state Kohn-Sham calculations are challenging.

Fragment-Based Calculations of Enzymatic Thermochemistry Require Dielectric Boundary Conditions.

Electronic structure calculations on enzymes require hundreds of atoms to obtain converged results, but fragment-based approximations offer a cost-effective solution. We present calculations on enzyme models containing 500-600 atoms using the many-body expansion, comparing to benchmarks in which the entire enzyme-substrate complex is described at the same level of density functional theory. When the amino acid fragments contain ionic side chains, the many-body expansion oscillates under vacuum boundary conditions but rapid convergence is restored using low-dielectric boundary conditions. This implies that full-system calculations in the gas phase are inappropriate benchmarks for assessing errors in fragment-based approximations. A three-body protocol retains sub-kilocalorie per mole fidelity with respect to a supersystem calculation, as does a two-body calculation combined with a full-system correction at a low-cost level of theory. These protocols pave the way for application of high-level quantum chemistry to large systems via rigorous, ab initio treatment of many-body polarization.

Slater transition methods for core-level electron binding energies.

Methods for computing core-level ionization energies using self-consistent field (SCF) calculations are evaluated and benchmarked. These include a "full core hole" (or "ΔSCF") approach that fully accounts for orbital relaxation upon ionization, but also methods based on Slater's transition concept in which the binding energy is estimated from an orbital energy level that is obtained from a fractional-occupancy SCF calculation. A generalization that uses two different fractional-occupancy SCF calculations is also considered. The best of the Slater-type methods afford mean errors of 0.3-0.4 eV with respect to experiment for a dataset of K-shell ionization energies, a level of accuracy that is competitive with more expensive many-body techniques. An empirical shifting procedure with one adjustable parameter reduces the average error below 0.2 eV. This shifted Slater transition method is a simple and practical way to compute core-level binding energies using only initial-state Kohn-Sham eigenvalues. It requires no more computational effort than ΔSCF and may be especially useful for simulating transient x-ray experiments where core-level spectroscopy is used to probe an excited electronic state, for which the ΔSCF approach requires a tedious state-by-state calculation of the spectrum. As an example, we use Slater-type methods to model x-ray emission spectroscopy.

Birth of the Hydrated Electron via Charge-Transfer-to-Solvent Excitation of Aqueous Iodide.

A primary means to generate hydrated electrons in laboratory experiments is excitation to the charge-transfer-to-solvent (CTTS) state of a solute such as I-(aq), but this initial step in the genesis of e-(aq) has never been simulated directly using ab initio molecular dynamics. We report the first such simulations, combining ground- and excited-state simulations of I-(aq) with a detailed analysis of fluctuations in the Coulomb potential experienced by the nascent solvated electron. What emerges is a two-step picture of the evolution of e-(aq) starting from the CTTS state: I-(aq) + hν → I-*(aq) → I•(aq) + e-(aq). Notably, the equilibrated ground state of e-(aq) evolves from I-*(aq) without any nonadiabatic transitions, simply as a result of solvent reorganization. The methodology used here should be applicable to other photochemical electron transfer processes in solution, an important class of problems directly relevant to photocatalysis and energy transfer.

Systematic Evaluation of Counterpoise Correction in Density Functional Theory.

A widespread belief persists that the Boys-Bernardi function counterpoise (CP) procedure "overcorrects" supramolecular interaction energies for the effects of basis-set superposition error. To the extent that this is true for correlated wave function methods, it is usually an artifact of low-quality basis sets. The question has not been considered systematically in the context of density functional theory, however, where basis-set convergence is generally less problematic. We present a systematic assessment of the CP procedure for a representative set of functionals and basis sets, considering both benchmark data sets of small dimers and larger supramolecular complexes. The latter include layered composite polymers with ∼150 atoms and ligand-protein models with ∼300 atoms. Provided that CP correction is used, we find that intermolecular interaction energies of nearly complete-basis quality can be obtained using only double-ζ basis sets. This is less expensive as compared to triple-ζ basis sets without CP correction. CP-corrected interaction energies are less sensitive to the presence of diffuse basis functions as compared to uncorrected energies, which is important because diffuse functions are expensive and often numerically problematic for large systems. Our results upend the conventional wisdom that CP "overcorrects" for basis-set incompleteness. In small basis sets, CP correction is mandatory in order to demonstrate that the results do not rest on error cancellation.

Data-driven learning of narcosis mode of action identifies a CNS transcriptional signature shared between whole organism Caenorhabditis elegans and a fish gill cell line.

With the large numbers of man-made chemicals produced and released in the environment, there is a need to provide assessments on their potential effects on environmental safety and human health. Current regulatory frameworks rely on a mix of both hazard and risk-based approaches to make safety decisions, but the large number of chemicals in commerce combined with an increased need to conduct assessments in the absence of animal testing makes this increasingly challenging. This challenge is catalysing the use of more mechanistic knowledge in safety assessment from both in silico and in vitro approaches in the hope that this will increase confidence in being able to identify modes of action (MoA) for the chemicals in question. Here we approach this challenge by testing whether a functional genomics approach in C. elegans and in a fish cell line can identify molecular mechanisms underlying the effects of narcotics, and the effects of more specific acting toxicants. We show that narcosis affects the expression of neuronal genes associated with CNS function in C. elegans and in a fish cell line. Overall, we believe that our study provides an important step in developing mechanistically relevant biomarkers which can be used to screen for hazards, and which prevent the need for repeated animal or cross-species comparisons for each new chemical.

High harmonic spectra computed using time-dependent Kohn-Sham theory with Gaussian orbitals and a complex absorbing potential.

High harmonic spectra for H2 and H2 + are simulated by solving the time-dependent Kohn-Sham equation in the presence of a strong laser field using an atom-centered Gaussian representation of the density and a complex absorbing potential. The latter serves to mitigate artifacts associated with the finite extent of the basis functions, including spurious reflection of the outgoing electronic wave packet. Interference between the outgoing and reflected waves manifests as peak broadening in the spectrum as well as the appearance of spurious high-energy peaks after the harmonic progression has terminated. We demonstrate that well-resolved spectra can be obtained through the use of an atom-centered absorbing potential. As compared to grid-based algorithms, the present approach is more readily extensible to larger molecules.

Detection and Correction of Delocalization Errors for Electron and Hole Polarons Using Density-Corrected DFT.

Modeling polaron defects is an important aspect of computational materials science, but the description of unpaired spins in density functional theory (DFT) often suffers from delocalization error. To diagnose and correct the overdelocalization of spin defects, we report an implementation of density-corrected (DC-)DFT and its analytic energy gradient. In DC-DFT, an exchange-correlation functional is evaluated using a Hartree-Fock density, thus incorporating electron correlation while avoiding self-interaction error. Results for an electron polaron in models of titania and a hole polaron in Al-doped silica demonstrate that geometry optimization with semilocal functionals drives significant structural distortion, including the elongation of several bonds, such that subsequent single-point calculations with hybrid functionals fail to afford a localized defect even in cases where geometry optimization with the hybrid functional does localize the polaron. This has significant implications for traditional workflows in computational materials science, where semilocal functionals are often used for structure relaxation. DC-DFT calculations provide a mechanism to detect situations where delocalization error is likely to affect the results.

State-specific solvation for restricted active space spin-flip (RAS-SF) wave functions based on the polarizable continuum formalism.

The restricted active space spin-flip (RAS-SF) formalism is a particular form of single-reference configuration interaction that can describe some forms of strong correlation at a relatively low cost and which has recently been formulated for the description of charge-transfer excited states. Here, we introduce both equilibrium and nonequilibrium versions of a state-specific solvation correction for vertical transition energies computed using RAS-SF wave functions, based on the framework of a polarizable continuum model (PCM). Ground-state polarization is described using the solvent's static dielectric constant and in the nonequilibrium solvation approach that polarization is modified upon vertical excitation using the solvent's optical dielectric constant. Benchmark calculations are reported for well-studied models of photo-induced charge transfer, including naphthalene dimer, C2H4⋯C2F4, pentacene dimer, and perylene diimide (PDI) dimer, several of which are important in organic photovoltaic applications. For the PDI dimer, we demonstrate that the charge-transfer character of the excited states is enhanced in the presence of a low-dielectric medium (static dielectric constant ɛ0 = 3) as compared to a gas-phase calculation (ɛ0 = 1). This stabilizes mechanistic traps for singlet fission and helps to explain experimental singlet fission rates. We also examine the effects of nonequilibrium solvation on charge-separated states in an intramolecular singlet fission chromophore, where we demonstrate that the energetic ordering of the states changes as a function of solvent polarity. The RAS-SF + PCM methodology that is reported here provides a framework to study charge-separated states in solution and in photovoltaic materials.