The kappa opioid receptor (KOR) is an important target for pain and depression therapeutics that lack harmful and addictive qualities of existing medications. We present a model for the binding of morphinan ligands and JDTic to the JDTic/KOR crystal structure based on an atomic level description of the water structure within its active site. The model contains two key interaction motifs that are supported by experimental evidence. The first is the formation of a salt bridge between the ligand and Asp 1383.32 in transmembrane domain (TM) 3. The second is the stabilization by the ligand of two high energy, isolated, and ice-like waters near TM5 and TM6. This model is incorporated via energetic terms into a new empirical scoring function, WScore, designed to assess interactions between ligands and localized water in a binding site. Pairing WScore with the docking program Glide discriminates known active KOR ligands from large sets of decoy molecules much better than Glide’s older generation scoring functions, SP and XP. We also use rigorous free energy perturbation calculations to provide evidence for the proposed mechanism of interaction between ligands and KOR. The molecular description of ligand binding in KOR should provide a good starting point for future drug discovery efforts for this receptor.

The cation in the electrolyte of the dye-sensitized solar cell (DSSC) has a profound effect on electron trapping and transport behavior in TiO2 nanocrystalline film; this is one of the important factors that determines the overall efficiency of DSSCs. Here, we present a quantum mechanical investigation on the structures and energetics of proton-induced electron trap states and the thermodynamical barrier heights for the ambipolar diffusion of proton/electron pair using a large cluster model for the computations. Our calculations indicate that protons react with TiO2 to form covalent O–H bonds. This is in contrast to the reaction of Li+ with TiO2, in which case the alkali metal is more accurately described as a simple coordinating cation. The covalent O–H bonding leads both to deeper electron trap states and to significantly higher barriers for the diffusion of carriers. These results are qualitatively consistent with experimental observations, and they extend our understanding of the cation effect in DSSCs at an atomic level of detail.

Acid dissociation constants are computed with density functional theory (DFT) for a series of ten first-row octahedral hexaaqua transition metal complexes at the B3LYP/LACV3P** level of theory. These results are then scaled, primarily to correct for basis set effects (as in previous work on predicting pKa’s in organic systems1−5). Finally, localized orbital corrections (LOCs), developed by fitting properties such as ionization potentials, electron affinities, and ligand removal energies in prior publications,3,4,6,7 are applied without any further parameter adjustment. The combination of a single scale factor with the DBLOC (localized orbital corrections for first row transition metals) corrections (and thus a single adjustable parameter in all) improves the mean unsigned error from 5.7 pKa units (with no parameters) to 0.9 pKa units (maximum error 2.2 pKa units), which is close to chemical accuracy for this type of system. These results provide further encouragement with regard to the ability of the B3LYP-DBLOC model to provide accurate and robust results for DFT calculations on transition metal containing species.

Robust homology modeling to atomic-level accuracy requires in the general case successful prediction of protein loops containing small segments of secondary structure. Further, as loop prediction advances to success with larger loops, the exclusion of loops containing secondary structure becomes awkward. Here, we extend the applicability of the Protein Local Optimization Program (PLOP) to loops up to 17 residues in length that contain either helical or hairpin segments. In general, PLOP hierarchically samples conformational space and ranks candidate loops with a high-quality molecular mechanics force field. For loops identified to possess α-helical segments, we employ an alternative dihedral library composed of (ϕ, ψ) angles commonly found in helices. The alternative library is searched over a user-specified range of residues that defines the helical bounds. The source of these helical bounds can be from popular secondary structure prediction software or from analysis of past loop predictions where a propensity to form a helix is observed. Due to the maturity of our energy model, the lowest energy loop across all experiments can be selected with an accuracy of sub-Ångström RMSD in 80% of the cases, 1.0 to 1.5 Å RMSD in 14% of the cases, and poorer than 1.5 Å RMSD in 6% of the cases. The effectiveness of our current methods in predicting hairpin-containing loops is explored with hairpins up to 13 residues in length and again reaching an accuracy of sub-Ångström RMSD in 83% of the cases, 1.0 to 1.5 Å RMSD in 10% of the cases, and poorer than 1.5 Å RMSD in 7% of the cases. Finally, we explore the effect of an imprecise surrounding environment, in which side chains, but not the backbone, are initially in perturbed geometries. In these cases, loops perturbed to 3 Å RMSD from the native environment were restored to their native conformation with sub-Ångström RMSD.

We have developed a cluster model of a TiO2 nanoparticle in the dye-sensitized solar cell and used first-principles quantum chemistry, coupled with a continuum solvation model, to compute structures and energetics of key electronic and structural intermediates and transition states. Our results suggest the existence of shallow surface trapping states induced by small cations and continuum solvent effect as well as the possibility of the existence of a surface band which is 0.3–0.5 eV below the conduction band edge. The results are in uniformly good agreement with experiment and establish the plausibility of an ambipolar model of electron diffusion in which small cations, such as Li+, diffuse alongside the current carrying electrons in the device, stabilizing shallowing trapping states, facilitating diffusion from one of these states to another, in a fashion that is essential to the functioning of the cell.

The modeling of the conformational properties of conjugated polymers entails a unique challenge for classical force fields. Conjugation imposes strong constraints upon bond rotation. Planar configurations are favored, but the concomitantly shortened bond lengths result in moieties being brought into closer proximity than usual. The ensuing steric repulsions are particularly severe in the presence of side chains, straining angles, and stretching bonds to a degree infrequently found in nonconjugated systems. We herein demonstrate the resulting inaccuracies by comparing the LMP2-calculated inter-ring torsion potentials for a series of substituted stilbenes and bithiophenes to those calculated using standard classical force fields. We then implement adjustments to the OPLS-2005 force field in order to improve its ability to model such systems. Finally, we show the impact of these changes on the dihedral angle distributions, persistence lengths, and conjugation length distributions observed during molecular dynamics simulations of poly[2-methoxy-5-(2′-ethylhexyloxy)-p-phenylene vinylene] (MEH-PPV) and poly 3-hexylthiophene (P3HT), two of the most widely used conjugated polymers.

Single-electron reduction half potentials of 95 octahedral fourth-row transition metal complexes binding a diverse set of ligands have been calculated at the unrestricted pseudospectral B3LYP/LACV3P level of theory in a continuum solvent. Through systematic comparison of experimental and calculated potentials, it is determined that B3LYP strongly overbinds the d-manifold when the metal coordinates strongly interacting ligands and strongly underbinds the d-manifold when the metal coordinates weakly interacting ligands. These error patterns give rise to an extension of the localized orbital correction (LOC) scheme previously developed for organic molecules and which was recently extended to the spin-splitting properties of organometallic complexes. Mean unsigned errors in B3LYP redox potentials are reduced from 0.40 ± 0.20 V (0.88 V max error) to 0.12 ± 0.09 V (0.34 V max error) using a simple seven-parameter model. Although the focus of this article is on redox properties of transition metal complexes, we have found that applying our previous spin-splitting LOC model to an independent test set of oxidized and reduced complexes that are also spin-crossover complexes correctly reverses the ordering of spin states obtained with B3LYP. Interesting connections are made between redox and spin-splitting parameters with regard to the spectrochemical series and in their combined predictive power for properly closing the thermodynamic cycle of d-electron transitions in a transition metal complex. Results obtained from our large and diverse databases of spin-splitting and redox properties suggest that, while the error introduced by single reference B3LYP for simple multireference systems, like mononuclear transition metal complexes, remains significant, at around 2–5 kcal/mol, the dominant error, at around 10–20 kcal/mol, is in B3LYP’s prediction of metal–ligand binding. Application of the LOC scheme to the rate-determining hydrogen atom transfer step in substrate hydroxylation by cytochrome P450 shows that this approach is able to correct the B3LYP barriers in comparison to recent kinetics experiments.

Average ligand removal enthalpies of 30 differently coordinated mono-nuclear fourth-row transition metal complexes taken from a database recently considered by Johnson and Becke [Can. J. Chem., 2009, 8, 1369] have been computed in the gas phase using unrestricted pseudo-spectral (LACV3P) and fully analytic (qzvp(-g)) B3LYP including a recently developed empirical dispersion correction. Heats of formation of neutral singlet reactants and neutral, potentially high spin, products have been taken from NIST's Organometallic Thermochemistry Database. Comparison of B3LYP-MM//qzvp(-g) and experimental average ligand removal enthalpies reveals a systematic error in the reported experimental enthalpies for manganese-containing complexes which is verified with high-level, CCSD(T)-F12//family of cc-pVTZ, explicitly correlated coupled-cluster methods. Other B3LYP-MM//qzvp(-g) error patterns give rise to a d-block localized orbital correction (DBLOC) scheme containing six transferable parameters that correct the functional's description of metal–ligand bonding, cation-π, and dispersion interactions as well as metal and/or ligand multi-reference effects. Metal–ligand cation-π and dispersion interactions have been fit to the monopole/induced-dipole, , and induced-dipole/induced-dipole, , interaction functions, respectively. This DBLOC model has been built upon a previously determined set of metal atom parameters which are necessary to properly describe the free metal atom reaction products. The final DBLOC model brings the mean unsigned error of B3LYP-MM//qzvp(-g) from 3.74 ± 3.51 kcal/mol to 0.94 ± 0.68 kcal/mol and corrects the functional's under binding in nearly every case. Several important connections among DBLOC parameters have been made.

Raman spectra were recorded experimentally and calculated theoretically for bithiophene, terthiophene, and quaterthiophene samples as a function of excitation polarization. Distinct spectral signatures were assigned and correlated to the molecular/unit cell orientation as determined by X-ray diffraction. The ability to predict molecular/unit cell orientation within organic crystals using polarized Raman spectroscopy was evaluated by predicting the unit cell orientation in a simulated terthiophene crystal given a random set of simulated polarized Raman spectra. Polarized Raman spectroscopy offers a promising tool to quickly and economically determine the unit cell orientation in known organic crystals and crystalline thin films. Implications of our methodologies for studying individual molecule conformations are discussed.

The methane and toluene monooxygenase hydroxylases (MMOH and TMOH, respectively) have almost identical active sites, yet the physical and chemical properties of their oxygenated intermediates, designated P*, Hperoxo, Q, and Q* in MMOH and ToMOHperoxo in a subclass of TMOH, ToMOH, are substantially different. We review and compare the structural differences in the vicinity of the active sites of these enzymes and discuss which changes could give rise to the different behavior of Hperoxo and Q. In particular, analysis of multiple crystal structures reveals that T213 in MMOH and the analogous T201 in TMOH, located in the immediate vicinity of the active site, have different rotatory configurations. We study the rotational energy profiles of these threonine residues with the use of molecular mechanics (MM) and quantum mechanics/molecular mechanics (QM/MM) computational methods and put forward a hypothesis according to which T213 and T201 play an important role in the formation of different types of peroxodiiron(III) species in MMOH and ToMOH. The hypothesis is indirectly supported by the QM/MM calculations of the peroxodiiron(III) models of ToMOH and the theoretically computed Mössbauer spectra. It also helps explain the formation of two distinct peroxodiiron(III) species in the T201S mutant of ToMOH. Additionally, a role for the ToMOD regulatory protein, which is essential for intermediate formation and protein functioning in the ToMO system, is advanced. We find that the low quadrupole splitting parameter in the Mössbauer spectrum observed for a ToMOHperoxo intermediate can be explained by protonation of the peroxo moiety, possibly stabilized by the T201 residue. Finally, similarities between the oxygen activation mechanisms of the monooxygenases and cytochrome P450 are discussed.

Spin-splittings of 57 octahedral first-row transition metal complexes calculated with B3LYP are compared with a database of experimental spectra collected from the literature. A variety of transition metal centers in various oxidation states and multiplicities along with a number of different coordinating ligands are considered. Environmental effects have been included to enable reasonable quantitative comparison with experiment. The manifold of states is studied using initial guesses constructed from ligand field theory. A localized orbital correction (LOC) model, referred to as DBLOC-DFT (d-block localized orbital corrected density functional theory), systematically corrects B3LYP calculations using five parameters. The final results are a considerable improvement over conventional DFT, bringing the mean unsigned error (MUE) from 10.14 kcal/mol with a standard deviation of 4.56 to 1.98 kcal/mol with a standard deviation of 1.62. Depending on the relative multiplicities of the ground and excited states, it is shown that B3LYP*, which has 15% exact nonlocal exchange, can lead to larger errors with respect to experiment than B3LYP. Application to 7 complexes from Swart et al. [ J. Phys. Chem. A 2004, 108, 5479.] and 14 small-gap spin-crossover complexes, from the literature, shows the DBLOC model provides good agreement with a variety of experimental data.

A vast number of noncovalent interaction energies at the counterpoise corrected CCSD(T) level have been collected from the literature to build a diverse new data set. The whole data set, which consists of 2027 CCSD(T) energies, includes most of the published data at this level. A large subset of the data was then used to train a novel, B3LYP specific, empirical correction scheme for noncovalent interactions and basis set superposition error (abbreviated as B3LYP-MM). Results obtained with our new correction scheme were directly compared to benchmark results obtained with B3LYP-D3 and M06-2X (two popular density functionals designed specifically to accurately model noncovalent interactions). For noncovalent complexes dominated by dispersion or dipole-dipole interactions, all three tested methods give accurate results with the medium-sized aug-cc-pVDZ basis set with MUEs of 0.27 (B3LYP-MM), 0.32 (B3LYP-D3), and 0.47 kcal/mol (M06-2X) (with explicit counterpoise corrections). These results validate both B3LYP-D3 and M06-2X for interactions of this type using a much larger data set than was presented in prior work. However, our new dispersion correction scheme shows some clear advantages for dispersion and dipole-dipole dominated complexes with the small LACVP* basis set, which is very popular in use due to its low associated computational cost: The MUE for B3LYP-MM with the LACVP* basis set for this subset of complexes (without explicit counterpoise corrections) is only 0.28 kcal/mol, compared to 0.65 kcal/mol for M06-2X or 1.16 kcal/mol for B3LYP-D3. Additionally, our new correction scheme also shows major improvements in accuracy for hydrogen-bonded systems and for systems involving ionic interactions, for example, cation-π interactions. Compared to B3LYP-D3 and M06-2X, we also find that our new B3LYP-MM correction scheme gives results of higher or equal accuracy for a large data set of conformer energies of di- and tripeptides, sugars, and cysteine.

Accurate prediction of drug metabolism is crucial for drug design. Since a large majority of drugs’ metabolism involves P450 enzymes, we herein describe a computational approach, IDSite, to predict P450-mediated drug metabolism. To model induced-fit effects, IDSite samples the conformational space with flexible docking in Glide followed by two refinement stages using the Protein Local Optimization Program (PLOP). Sites of metabolism (SOMs) are predicted according to a physical-based score that evaluates the potential of atoms to react with the catalytic iron center. As a preliminary test, we present in this paper the prediction of hydroxylation and O-dealkylation sites mediated by CYP2D6 using two different models: a physical-based simulation model and a modification of this model in which a small number of parameters are fit to a training set. Without fitting any parameters to experimental data, the physical IDSite scoring recovers 83% of the experimental observations for 56 compounds with a very low false positive rate. With only four fitted parameters, the fitted IDSite was trained with a subset of 36 compounds and successfully applied to the other 20 compounds, recovering 94% of the experimental observations with high sensitivity and specificity for both sets.

The mechanism of water oxidation by a single site ruthenium oxygen evolving complex is investigated using fully unrestricted pseudospectral B3LYP with the effective core potential LACV3P in continuum solvent with some quantum mechanical waters. Guess wave functions have been used that allow greater flexibility in sampling different electronic configurations of the complex. Systematic comparison with experiment is improved using these guesses because they provide a complete analysis of the low energy manifold and help to alleviate the formal disconnect between theory and experiment in assigning Lewis structures for transition metal complexes. In agreement with results from the literature, the challenging 4e–and 4H+ oxidation of water is accomplished using a mechanism that features three proton coupled electron transfers, one electron transfer, one atom proton transfer (APT), and one ligand exchange (LE). Calculations on a large database of ruthenium complexes allows us to benchmark the computation of reduction half potentials and free energies of activation and to investigate systematic ligand variations and their effect on the reaction mechanism. Mean unsigned errors of reduction half potentials in comparison to experiment are generally small (100–200 mV). The APT and LE steps are found to be rate limiting with free energy barriers of 19.27 and 19.53 kcal/mol respectively, which is in excellent agreement with the ∼20 kcal/mol barrier obtained from experimental rate constants using classical transition state theory.

Our previous works have demonstrated the ability of our localized orbital correction (LOC) methodology to greatly improve the accuracy of various thermochemical properties at the stationary points of the density functional theory (DFT) reaction coordinate (RC). Herein, we extend this methodology from stationary points to the entire RC connecting any stationary points by developing continuous localized orbital corrections (CLOCs). We show that the resultant method, DFT-CLOC, is capable of producing RCs with far greater accuracy than uncorrected DFT and yet requires negligible computational cost beyond the uncorrected DFT calculations. Various post-Hartree−Fock (post-HF) reaction coordinate profiles were used, including a sigmatropic shift, Diels−Alder reaction, electrocyclization, carbon radical, and three hydrogen radical reactions to show that this method is robust across multiple reaction types of general interest.

We report the performance of eight density functionals (B3LYP, BPW91, OLYP, O3LYP, M06, M06-2X, PBE, and SVWN5) in two Gaussian basis sets (Wachters and Partridge-1 on iron atoms; cc-pVDZ on the rest of atoms) for prediction of the isomer shift (IS) and quadrupole splitting (QS) parameters of Mössbauer spectroscopy. Two sources of geometry (density functional theory optimized and X-ray) are used. Our data set consists of 31 iron-containing compounds (35 signals), the Mössbauer spectra of which were determined at liquid helium temperature and where the X-ray geometries are known. Our results indicate that the larger and uncontracted Partridge-1 basis set produces slightly more accurate linear correlations of electronic density used for prediction of IS and noticeably more accurate results for the QS parameters. We confirm and discuss the earlier observation of Noodleman and co-workers that different oxidation states of iron produce different IS calibration lines. The B3LYP and O3LYP functionals have the lowest errors for either IS or QS. BPW91, OLYP, PBE, and M06 have mixed success, whereas SVWN5 and M06-2X demonstrate the worst performance. Finally, our calibrations and conclusions regarding the best functional to compute the Mössbauer characteristics are applied to candidate structures for the peroxo and Q intermediates of the enzyme methane monooxygenase hydroxylase (MMOH) and are compared to experimental data in the literature.

Using a structure generated by induced fit modeling of the protein−ligand complex, the reaction path for hydrogen atom abstraction in P450 BM3 is studied by means of mixed QM/MM methods to determine the structures and energetics along the reaction path. The IFD structure is suitable for hydrogen atom abstraction at the ω−1 position. The electronic structures obtained are similar to those observed in P450 cam. We show that the barrier for the hydrogen abstraction step from QM/MM modeling is 13.3 kcal/mol in quartet and 15.6 kcal/mol in doublet. Although there is some strain energy present in the ligand, the activation barrier is not dramatically affected. A crystal water molecule, HOH502, plays a role as catalyst and decreases the activation barrier by about 2 kcal/mol and reaction energy by about 3−4 kcal/mol. To achieve reactive chemistry at the remaining experimentally observed positions in the hydrocarbon tail of the ligand, other structures would have to be utilized as a starting point for the reaction. Finally, the present results still leave open the question of whether DFT methods provide an accurate computation of the barrier height in the P450 hydrogen atom abstraction reaction.

Oligothiophenes are promising candidates as organic molecular wires. Density functional theory is employed to investigate eight oligothiophene series with various side chains, end groups, and spacers ranging in length from 3 to 12 monomers. Redox potentials are evaluated for a number of species on the basis of the thermodynamic cycle formalism (J. Phys. Chem. A 2002, 106, 7407) and agree well with the experimental results. It is confirmed that polarons rather than bipolarons play the role of charge carriers for charged oligomers with sufficiently long backbone. Our calculations also shed light on the detailed oxidization processes in cyclic voltammetry experiments and, hence, provide significant implications on the design of novel oligothiophene-based conductive materials.

Recent studies reveal that the core sequences of many proteins were nearly optimized for stability by natural evolution. Surface residues, by contrast, are not so optimized, presumably because protein function is mediated through surface interactions with other molecules. Here, we sought to determine the extent to which the sequences of protein ligand-binding and enzyme active sites could be predicted by optimization of scoring functions based on protein ligand-binding affinity rather than structural stability. Optimization of binding affinity under constraints on the folding free energy correctly predicted 83% of amino acid residues (94% similar) in the binding sites of two model receptor-ligand complexes, streptavidin-biotin and glucose-binding protein. To explore the applicability of this methodology to enzymes, we applied an identical algorithm to the active sites of diverse enzymes from the peptidase, β-gal, and nucleotide synthase families. Although simple optimization of binding affinity reproduced the sequences of some enzyme active sites with high precision, imposition of additional, geometric constraints on side-chain conformations based on the catalytic mechanism was required in other cases. With these modifications, our sequence optimization algorithm correctly predicted 78% of residues from all of the enzymes, with 83% similar to native (90% correct, with 95% similar, excluding residues with high variability in multiple sequence alignments). Furthermore, the conformations of the selected side chains were often correctly predicted within crystallographic error. These findings suggest that simple selection pressures may have played a predominant role in determining the sequences of ligand-binding and active sites in proteins.

This Perspective provides an overview of state-of-the-art ab initio quantum chemical methodology and applications. The methods that are discussed include coupled cluster theory, localized second-order Moller–Plesset perturbation theory, multireference perturbation approaches, and density functional theory. The accuracy of each approach for key chemical properties is summarized, and the computational performance is analyzed, emphasizing significant advances in algorithms and implementation over the past decade. Incorporation of a condensed-phase environment by means of mixed quantum mechanical/molecular mechanics or self-consistent reaction field techniques, is presented. A wide range of illustrative applications, focusing on materials science and biology, are discussed briefly.

We recently found that many residues in enzyme active sites can be computationally predicted by the optimization of scoring functions based on substrate binding affinity, subject to constraints on the geometry of catalytic residues and protein stability. Here, we explore the generality of this surprising observation. First, the impact of hydrogen-bonding networks necessary for catalysis on the accuracy of sequence optimization is assessed; incorporation of these networks, where relevant, into the set of catalytic constraints is found to be essential. Next, the impact of multiple substrate selectivity on sequence optimization is probed by carrying out independent calculations for complexes of deoxyribonucleoside kinases with various cognate ligands, revealing how simultaneous selection pressures determined active-site sequences of these enzymes. Including previous calculations on simpler enzymes, computational sequence optimization correctly predicts 76% of all active-site residues tested (86% correct, with 93% similar, for naturally conserved residues). In these studies, the ligand is fixed in its native conformation. To assess the applicability of these methods to de novo active-site design, the effect of small ligand motions around the native pose is also examined. Robustness of sequence accuracy for topologically similar poses is demonstrated for selected kinases, but not for a model peptidase. Based on these observations, we introduce the notion of the designability of an enzyme active site, a metric that may be used to guide the search for protein scaffolds suitable for the introduction of de novo activity for a desired chemical reaction.

Over the past several years, rapid advances in computational hardware, quantum chemical methods, and mixed quantum mechanics/molecular mechanics (QM/MM) techniques have made it possible to model accurately the interaction of ligands with metal-containing proteins at an atomic level of detail. In this paper, we describe the application of our computational methodology, based on density functional (DFT) quantum chemical methods, to two diiron-containing proteins that interact with dioxygen: methane monooxygenase (MMO) and hemerythrin (Hr). Although the active sites are structurally related, the biological function differs substantially. MMO is an enzyme found in methanotrophic bacteria and hydroxylates aliphatic C–H bonds, whereas Hr is a carrier protein for dioxygen used by a number of marine invertebrates. Quantitative descriptions of the structures and energetics of key intermediates and transition states involved in the reaction with dioxygen are provided, allowing their mechanisms to be compared and contrasted in detail. An in-depth understanding of how the chemical identity of the first ligand coordination shell, structural features, electrostatic and van der Waals interactions of more distant shells control ligand binding and reactive chemistry is provided, affording a systematic analysis of how iron-containing proteins process dioxygen. Extensive contact with experiment is made in both systems, and a remarkable degree of accuracy and robustness of the calculations is obtained from both a qualitative and quantitative perspective.

We elucidate the hydroxylation of camphor by cytochrome P450 with the use of density functional and mixed quantum mechanics/molecular mechanics methods. Our results reveal that the enzyme catalyzes the hydrogen-atom abstraction step with a remarkably low free-energy barrier. This result provides a satisfactory explanation for the experimental failure to trap the proposed catalytically competent high-valent heme Fe(IV) oxo (oxyferryl) species responsible for this hydroxylation chemistry. The primary and previously unappreciated contribution to stabilization of the transition state is the interaction of positively charged residues in the active-site cavity with carboxylate groups on the heme periphery. A similar stabilization found in dioxygen binding to hemerythrin, albeit with reversed polarity, suggests that this mechanism for controlling the relative energetics of redox-active intermediates and transition states in metalloproteins may be widespread in nature.

Average ligand removal enthalpies of 30 differently coordinated mono-nuclear fourth-row transition metal complexes taken from a database recently considered by Johnson and Becke [Can. J. Chem., 2009, 8, 1369] have been computed in the gas phase using unrestricted pseudo-spectral (LACV3P) and fully analytic (qzvp(-g)) B3LYP including a recently developed empirical dispersion correction. Heats of formation of neutral singlet reactants and neutral, potentially high spin, products have been taken from NIST's Organometallic Thermochemistry Database. Comparison of B3LYP-MM//qzvp(-g) and experimental average ligand removal enthalpies reveals a systematic error in the reported experimental enthalpies for manganese-containing complexes which is verified with high-level, CCSD(T)-F12//family of cc-pVTZ, explicitly correlated coupled-cluster methods. Other B3LYP-MM//qzvp(-g) error patterns give rise to a d-block localized orbital correction (DBLOC) scheme containing six transferable parameters that correct the functional's description of metal–ligand bonding, cation-π, and dispersion interactions as well as metal and/or ligand multi-reference effects. Metal–ligand cation-π and dispersion interactions have been fit to the monopole/induced-dipole, , and induced-dipole/induced-dipole, , interaction functions, respectively. This DBLOC model has been built upon a previously determined set of metal atom parameters which are necessary to properly describe the free metal atom reaction products. The final DBLOC model brings the mean unsigned error of B3LYP-MM//qzvp(-g) from 3.74 ± 3.51 kcal/mol to 0.94 ± 0.68 kcal/mol and corrects the functional's under binding in nearly every case. Several important connections among DBLOC parameters have been made.