The nature of H-H interaction between *ortho*-hydrogen atoms in planar biphenyl is investigated by two different atomic energy partitioning methods, namely fractional occupation iterative Hirshfeld (FOHI) and interacting quantum atoms (IQA), and compared with the traditional virial-based approach of quantum theory of atoms in molecules (QTAIM). In agreement with Bader's hypothesis of HH bonding, partitioning the atomic energy into intra-atomic and interatomic terms reveals that there is a net attractive interaction between the *ortho*-hydrogens in the planar biphenyl. This falsifies the classical view of steric repulsion between the hydrogens. In addition, in contrast to the traditional QTAIM energy analysis, both FOHI and IQA show that the total atomic energy of the *ortho*-hydrogens remains almost constant when they participate in the H-H interaction. Although, the interatomic part of atomic energy of the hydrogens plays a stabilizing role during the formation of the HH bond, it is almost compensated by the destabilizing effects of the intra-atomic parts and consequently, the total energy of the hydrogens remains constant. The trends in the changes of intra-atomic and interatomic energy terms of *ortho*-hydrogens during HH bond formation are very similar to those observed for the H_{2} molecule. © 2014 Wiley Periodicals, Inc.

In contrast to the classical view, both interacting quantum atoms and Hirshfeld atomic energy partitioning confirms Bader's hypothesis of H[]H bonding in the planar biphenyl; there is a net attractive interaction between the ortho-hydrogens. In other words, the H[]H bond paths (indicated by dashed lines) in the planar biphenyl are indicative of H[]H bonding.

Knowledge of the three-dimensional structures of glycans and glycoproteins is useful for a full understanding of molecular processes in which glycans are involved, such as antigen-recognition and virus infection, to name a few. Among the ubiquitous nuclei in glycan molecules, the ^{13}C nucleus is an attractive candidate for computation of theoretical chemical shifts at the quantum chemical level of theory to validate and determine glycan structures. For this purpose, it is important to determine, first, which carbons can be used as probes to sense conformational changes and, second, all factors that affect the computation of the shielding, at the density functional theory (DFT) level of theory, of those carbons. To answer such questions, we performed a series of analyses on low-energy conformations, obtained by sampling the glycosidic torsional angles (*ϕ*, *ψ*) every 10°, of 12 disaccharides. Our results provide evidence that: (i) the carbons that participate in the glycosidic linkage are the most sensitive probes with which to sense conformational changes of disaccharides; (ii) the rotation of the hydroxyl groups closest to the glycosidic linkage significantly affects the computation of the shieldings of the carbons that participate in the glycosidic linkage; (iii) it is not possible to obtain the shieldings of one disaccharide from the computed values of a different disaccharide or from those disaccharides that differ in the anomeric state; and (iv) a proper basis set distribution, a functional, and a step size, with which to sample the conformational space, are necessary to compute shieldings accurately and rapidly. © 2014 Wiley Periodicals, Inc.

Knowledge of the three-dimensional structures of carbohydrate molecules, as for maltose shown in the figure, is indispensable for a full understanding, at the molecular level, of the biological processes in which carbohydrates are involved. For this purpose, it is important to determine, first, which carbons can be used as probes to sense conformational changes and, second, all factors that affect the computation of the shielding, at the density functional theory (DFT) level of theory, of those carbons.

We present a detailed study of the basis set dependence of electronic g-tensors for transition metal complexes calculated using Kohn–Sham density functional theory. Focus is on the use of locally dense basis set schemes where the metal is treated using either the same or a more flexible basis set than used for the ligand sphere. The performance of all basis set schemes is compared to the extrapolated complete basis set limit results. Furthermore, we test the performance of the aug-cc-pVTZ-J basis set developed for calculations of NMR spin-spin and electron paramagnetic resonance hyperfine coupling constants. Our results show that reasonable results can be obtain when using small basis sets for the ligand sphere, and very accurate results are obtained when an aug-cc-pVTZ basis set or similar is used for all atoms in the complex. © 2014 Wiley Periodicals, Inc.

The calculation of the electronic g-tensor for electron paramagnetic resonance (EPR) is a promising route to aid experimental investigations, especially within bio-inorganic chemistry. However, as the number of basis functions greatly increase for compounds containing *d*-block elements, it would be desirable if smaller basis set could be used for the ligands in a so-called locally dense basis set approach. This article reports the accuracy of several locally dense basis set schemes and compare these to an extrapolated complete basis set value.

The physisorption of water on graphene is investigated with the hybrid density functional theory (DFT)-functional B3LYP combined with empirical corrections, using moderate-sized basis sets such as 6-31G(d). This setup allows to model the interaction of water with graphene going beyond the quality of classical or semiclassical simulations, while still keeping the computational costs under control. Good agreement with respect to Coupled Cluster with singles and doubles excitations and perturbative triples (CCSD(T)) results is achieved for the adsorption of a single water molecule in a benchmark with two DFT-functionals (Perdew/Burke/Ernzerhof (PBE), B3LYP) and Grimme's empirical dispersion and counterpoise corrections. We apply the same setting to graphene supported by epitaxial hexagonal boron nitride (h-BN), leading to an increased interaction energy. To further demonstrate the achievement of the empirical corrections, we model, entirely from first principles, the electronic properties of graphene and graphene supported by h-BN covered with different amounts of water (one, 10 water molecules per cell and full coverage). The effect of h-BN on these properties turns out to be negligibly small, making it a good candidate for a substrate to grow graphene on. © 2014 Wiley Periodicals, Inc.

The adsorption of water on graphene is computationally investigated via density functional theory combined with empirical corrections. This allows for going beyond the quality of classical or semiclassical simulations, while still keeping the computational costs under control. To model the water adsorption, we used 1 and 10 water molecules per cell, as well as a full coverage of the graphene surface. Additionally, we apply the same setup to hexagonal boron nitride supported graphene.

The flexible-boundary (FB) quantum mechanical/molecular mechanical (QM/MM) scheme accounts for partial charge transfer between the QM and MM subsystems. Previous calculations have demonstrated excellent performance of FB-QM/MM in geometry optimizations. This article reports an implementation to extend FB-QM/MM to molecular dynamics simulations. To prevent atoms from getting unreasonably close, which can lead to polarization catastrophe, empirical correcting functions are introduced to provide additive penalty energies for the involved atom pairs and to improve the descriptions of the repulsive exchange forces in FB-QM/MM calculations. Test calculations are carried out for chloride, lithium, sodium, and ammonium ions solvated in water. Comparisons with conventional QM/MM calculations suggest that the FB treatment provides reasonably good results for the charge distributions of the atoms in the QM subsystems and for the solvation shell structural properties, albeit smaller QM subsystems have been used in the FB-QM/MM dynamics simulations. © 2014 Wiley Periodicals, Inc.

Flexible-boundary QM/MM allows on-the-fly exchange of partial charges between the QM and MM subsystems in molecular dynamics. An average total charge of −0.9 e is observed for a chloride ion and its first solvation shell treated by QM, while on average the bulk water modeled by MM carries a total charge of −0.1 e.

The presented program package, Conformational Analysis and Search Tool (CAST) allows the accurate treatment of large and flexible (macro) molecular systems. For the determination of thermally accessible minima CAST offers the newly developed TabuSearch algorithm, but algorithms such as Monte Carlo (MC), MC with minimization, and molecular dynamics are implemented as well. For the determination of reaction paths, CAST provides the PathOpt, the Nudge Elastic band, and the umbrella sampling approach. Access to free energies is possible through the free energy perturbation approach. Along with a number of standard force fields, a newly developed symmetry-adapted perturbation theory-based force field is included. Semiempirical computations are possible through DFTB+ and MOPAC interfaces. For calculations based on density functional theory, a Message Passing Interface (MPI) interface to the Graphics Processing Unit (GPU)-accelerated TeraChem program is available. The program is available on request. © 2014 Wiley Periodicals, Inc.

The program package Conformational Analysis and Search Tool (CAST) provides many approaches for the description of large and flexible (macro) molecules. For the determination of thermally accessible minima, it contains the standard approaches molecular dynamics or Monte Carlo and the new TabuSearch-based global optimization routine. Reaction paths can be determined via nudged elastic band or PathOpt. Beside many standard force fields, CAST includes the SAPT-FF force field. Interfaces to MOPAC and TeraChem are also available.

The asymmetric Aza-Michael addition of homochiral lithium benzylamides to α,β-unsaturated esters represents an extended protocol to obtain enantioenriched β-amino esters. An exhaustive mechanistic revision of the originally proposed mechanism is reported, developing a quantum mechanics/molecular mechanics protocol for the asymmetric Aza-Michael reaction of homochiral lithium benzylamides. Explicit and implicit solvent schemes were considered, together with a proper account of long-range dispersion forces, evaluated through a density functional theory benchmark of different functionals. Theoretical results showed that the diastereoselectivity is mainly controlled by the *N*-α-methylbenzyl moiety placing, deriving a *Si*/*Re* 99:1 diastereoselective ratio, in good agreement with reported experimental results. The main transition state geometries are two transition state conformers in a “V-stacked” orientation of the amide's phenyl rings, differing in the tetrahydrofuran molecule arrangement coordinated to the metal center. Extensive conformational sampling and quantum-level refinement give reasonable good speed/accuracy results, allowing this protocol to be extended to other similar Aza-Michael reaction systems. © 2014 Wiley Periodicals, Inc.

The asymmetric Aza-Michael addition of homochiral lithium benzylamides to α,β-unsaturated esters represents an extended protocol to obtain enantioenriched β-amino esters. A QM/MM transition state protocol is presented, revising the original proposed mechanism. Theoretical results a *Si*/*Re* 99:1 diastereoselective ratio, in good agreement with experimental results, is reported. Two TS conformers in a “V-stacked” orientation of the amide's phenyl rings, differing in the THF molecule arrangement coordinated to lithium, are the most suitable TS geometries.

Shape-based virtual screening is an established and effective method for identifying small molecules that are similar in shape and function to a reference ligand. We describe a new method of shape-based virtual screening, volumetric aligned molecular shapes (VAMS). VAMS uses efficient data structures to encode and search molecular shapes. We demonstrate that VAMS is an effective method for shape-based virtual screening and that it can be successfully used as a prefilter to accelerate more computationally demanding search algorithms. Unique to VAMS is a novel minimum/maximum shape constraint query for precisely specifying the desired molecular shape. Shape constraint searches in VAMS are particularly efficient and millions of shapes can be searched in a fraction of a second. We compare the performance of VAMS with two other shape-based virtual screening algorithms a benchmark of 102 protein targets consisting of more than 32 million molecular shapes and find that VAMS provides a competitive trade-off between run-time performance and virtual screening performance. © 2014 Wiley Periodicals, Inc.

Volumetric aligned molecular shapes provide a way to screen libraries of molecular shapes that approaches the speed of the fastest shape-based methods and the accuracy of the most successful shape-based methods which are orders of magnitude slower. Volumetric aligned molecular shapes also offer a novel minimum/maximum shape constraint search that allows the user to precisely specify the desired shape and search millions of shapes in a fraction of a second.

Chiral discrimination by nuclear magnetic resonance (NMR) spectroscopy might be achieved through the pseudo-scalar derived from the dipole shielding polarizability tensor. Coupled Cluster Singles and Doubles-Quadratic Response (CCSD-QR) calculations inside the continuous translation of the origin of the current density formalism have been carried out to determine the effects of basis set, electron correlation, and gauge translation on the determination of this magnitude in oxaziridine derivatives. Inclusion of electronic correlation is needed for adequately describing the pseudo-scalar for the heavier nuclei, making CCSD a rigorous and affordable method to compute these high order properties in medium-sized molecules. The observable magnitudes for chiral discrimination (produced RF voltage and required electric field) are calculated. Half of the considered molecules show values of the observable magnitudes near the lower limit for experimental detection. Nuclei ^{19}F, ^{31}P, and ^{79}Br produce the largest values of RF voltage (50–80 nV). Moreover, ^{31}P and ^{79}Br are the nuclei requiring smallest electric fields (3 MVm^{−1}) to separate the NMR signals, being then suitable for both the techniques. © 2014 Wiley Periodicals, Inc.

Chiral discrimination by NMR spectroscopy might be achieved through the pseudo-scalar derived from the dipole shielding polarizability tensor, which has opposite sign in each enantiomer and is zero for achiral molecules. An accurate theoretical description of the magnitude is of fundamental importance to be susceptible of being unequivocally confirmed by experiment. CCSD calculations of the pseudo-scalar in oxaziridine derivatives show important effects caused by the chiral nuclei ^{19}F and ^{31}P.

Coarse-grained molecular dynamics (CGMD) simulations with the MARTINI force field were performed to reproduce the protein–ligand binding processes. We chose two protein–ligand systems, the levansucrase–sugar (glucose or sucrose), and LinB–1,2-dichloroethane systems, as target systems that differ in terms of the size and shape of the ligand-binding pocket and the physicochemical properties of the pocket and the ligand. Spatial distributions of the Coarse-grained (CG) ligand molecules revealed potential ligand-binding sites on the protein surfaces other than the real ligand-binding sites. The ligands bound most strongly to the real ligand-binding sites. The binding and unbinding rate constants obtained from the CGMD simulation of the levansucrase–sucrose system were approximately 10 times greater than the experimental values; this is mainly due to faster diffusion of the CG ligand in the CG water model. We could obtain dissociation constants close to the experimental values for both systems. Analysis of the ligand fluxes demonstrated that the CG ligand molecules entered the ligand-binding pockets through specific pathways. The ligands tended to move through grooves on the protein surface. Thus, the CGMD simulations produced reasonable results for the two different systems overall and are useful for studying the protein–ligand binding processes. © 2014 Wiley Periodicals, Inc.

Coarse-grained molecular dynamics simulations with the MARTINI force field were performed to reproduce the protein–ligand binding processes. Spatial distributions of the CG ligand molecules revealed potential ligand-binding sites on the protein surfaces other than the real ligand-binding sites. The ligands bound most strongly to the real ligand-binding sites. Analysis of the ligand fluxes demonstrated that the CG ligand molecules tended to enter the ligand-binding pockets through grooves on the protein surfaces.

The spectroscopic constants and absorption spectra of neutral and charged diatomic molecules of group 11 and 14 elements formulated as [M_{2}]^{+/0/−} (M = Cu, Ag, Au), and [E_{2}]^{+/0/−} (E = C, Si, Ge, Sn, Pb) have been calculated at the PBE0/Def2-QZVPP level of theory. The electronic and bonding properties of the diatomics have been analyzed by natural bond orbital analysis approach and topology analysis by the atoms in molecules method. Particular emphasis was given on the absorption spectra of the diatomic species, which were simulated by time-dependent density functional theory calculations employing the hybrid Coulomb-attenuating CAM-B3LYP density functional. The simulated absorption spectra of the [M_{2}]^{+/0/−} (M = Cu, Ag, Au) and [E_{2}]^{+/0/−} (E = C, Si, Ge, Sn, Pb) species are in close resemblance with the experimentally observed spectra whenever available. The neutral M_{2} and E_{2} diatomics strongly absorb in the ultraviolet region, given rise to UVC, UVA and in a few cases UVB absorptions. In a few cases, weak absorbion bands also occur in the visible region. The absorption bands have thoroughly been analyzed and assignments of the contributing principal electronic transitions associated to individual excitations have been made. © 2014 Wiley Periodicals, Inc.

The spectroscopic constants and absorption spectra of neutral and charged diatomic molecules of group 11 and 14 elements formulated as [M_{2}]^{+/0/−} (M = Cu, Ag, Au), and [E_{2}]^{+/0/−} (E = C, Si, Ge, Sn, Pb) have been thoroughly investigated by means of electronic structure calculation methods at the DFT and TDDFT levels.

By performing MP2/aug-cc-pVTZ *ab initio* calculations for a large set of dimer systems possessing a RH hydridic bond involved in diverse types of intermolecular interactions (dihydrogen bonds, hydride halogen bonds, hydride hydrogen bonds, and charge-assisted hydride hydrogen bonds), we show that this is rather an elongation than a shortening that a hydride bond undergoes on interaction. Contrary to what might have been expected on the basis of studies in uniform electric field, this elongation is accompanied by a blue instead of red shift of the RH stretching vibration frequency. We propose that the “additional” elongation of the RH hydridic bond results from the significant charge outflow from the sigma bonding orbital of RH that weakens this bond. The more standard red shift obtained for stronger complexes is explained by means of the Hermansson's formula and the particularly strong electric field produced by the H-acceptor molecule. © 2014 Wiley Periodicals, Inc.

The elongation of a hydride bond on its interaction seems to be much more typical effect than its shortening. Contrary to what might have been expected on the basis of studies in uniform electric field, this elongation is accompanied by a blue instead of red shift of the RH stretching vibration frequency. The “additional” elongation of the RH hydridic bond results from the significant charge outflow from the sigma bonding orbital of RH that weakens this bond.

In proteins with buried active sites, understanding how ligands migrate through the tunnels that connect the exterior of the protein to the active site can shed light on substrate specificity and enzyme function. A growing body of evidence highlights the importance of protein flexibility in the binding site on ligand binding; however, the influence of protein flexibility throughout the body of the protein during ligand entry and egress is much less characterized. We have developed a novel tunnel prediction and evaluation method named IterTunnel, which includes the influence of ligand-induced protein flexibility, guarantees ligand egress, and provides detailed free energy information as the ligand proceeds along the egress route. IterTunnel combines geometric tunnel prediction with steered molecular dynamics in an iterative process to identify tunnels that open as a result of ligand migration and calculates the potential of mean force of ligand egress through a given tunnel. Applying this new method to cytochrome P450 2B6, we demonstrate the influence of protein flexibility on the shape and accessibility of tunnels. More importantly, we demonstrate that the ligand itself, while traversing through a tunnel, can reshape tunnels due to its interaction with the protein. This process results in the exposure of new tunnels and the closure of preexisting tunnels as the ligand migrates from the active site. © 2014 Wiley Periodicals, Inc.

IterTunnel combines geometric tunnel prediction with steered MD to incorporate ligand migration and protein flexibility into tunnel prediction. We demonstrate that the ligand itself can reshape tunnels due to its interaction with the protein resulting in the exposure of new, energetically favorable tunnels.

Proteins are often characterized in terms of their primary, secondary, tertiary, and quaternary structure. Algorithms such as define secondary structure of proteins (DSSP) can automatically assign protein secondary structure based on the backbone hydrogen-bonding pattern. However, the assignment of secondary structure elements (SSEs) becomes a challenge when only the Cα coordinates are available. In this work, we present protein C-alpha secondary structure output (PCASSO), a fast and accurate program for assigning protein SSEs using only the Cα positions. PCASSO achieves ∼95% accuracy with respect to DSSP and takes ∼0.1 s using a single processor to analyze a 1000 residue system with multiple chains. Our approach was compared with current state-of-the-art Cα-based methods and was found to outperform all of them in both speed and accuracy. A practical application is also presented and discussed. © 2014 Wiley Periodicals, Inc.

Protein secondary structure elements (SSEs) are typically assigned based on backbone hydrogen-bonding patterns. However, when it comes to assigning SSEs using only the Cα positions, the current state-of-the-art is lacking in both accuracy and speed. To this end, protein C-alpha secondary structure output (PCASSO) is presented—a fast and accurate Cα-based SSE assignment tool that can be used for universal SSE assignments, high-throughput SSE studies, analysis of coarse-grained simulations, and so forth.

The reliability and accuracy of selfconsistent-charge density-functional tightbinding (SCCDFTB) models for describing the structure, energetics, charge distributions, and vibrational frequencies of anionic water clusters have been comprehensively evaluated by comparison of their predictions with results of MP2/aug-cc-pVTZ and CCSD(T)/aug-cc-pVQZ calculations. On page 1707 (DOI: 10.1002/jcc.23677), Soran Jahangiri, Lemin Cai, and Gilles H. Peslherbe report the SCC-DFTB model is found to perform particularly well, at a fraction of the computational cost, especially when recent corrections for hydrogen bonding and charge transfer are included.

Path coordinates are a useful construct to drive systems during the simulation of complex reactions involving many degrees of freedom to obtain the associated free energy changes. Kirill Zinovjev and Iñaki Tuñón report on page 1672 (DOI: 10.1002/jcc.23673) that consideration of the variable metric tensor results in well-behaved coordinates that provides good transition state ensembles for the processes under consideration. The application is illustrated with the analysis of an enzymatic reaction studied by means of QM/MM methods.

The magnetic coupling in transition metal compounds with more than one unpaired electron per magnetic center has been studied with multiconfigurational perturbation theory. The usual shortcomings of these methodologies (severe underestimation of the magnetic coupling) have been overcome by describing the Slater determinants with a set of molecular orbitals that maximally resemble the natural orbitals of a high-level multiconfigurational reference configuration interaction calculation. These orbitals have significant delocalization tails onto the bridging ligands and largely increase the coupling strengths in the perturbative calculation. © 2014 Wiley Periodicals, Inc.

Taking into account the ionic state in the optimization procedure of the molecular orbitals results in slightly more delocalized magnetic orbitals, and hence, repairs the underestimation of the magnetic coupling commonly observed for multiconfigurational perturbation theory.

Path-based reaction coordinates constitute a valuable tool for free-energy calculations in complex processes. When a reference path is defined by means of collective variables, a nonconstant distance metric that incorporates the nonorthonormality of these variables should be taken into account. In this work, we show that, accounting for the correct metric tensor, these kind of variables can provide iso-hypersurfaces that coincide with the iso-committor surfaces and that activation free energies equal the value that would be obtained if the committor function itself were used as reaction coordinate. The advantages of the incorporation of the variable metric tensor are illustrated with the analysis of the enzymatic reaction catalyzed by isochorismate-pyruvate lyase. Hybrid QM/MM techniques are used to obtain the free energy profile and to analyze reactive trajectories initiated at the transition state. For this example, the committor histogram is peaked at 0.5 only when a variable metric tensor is incorporated in the definition of the path-based coordinate. © 2014 Wiley Periodicals, Inc.

Path coordinates are a useful construct to drive systems during the simulation of complex reactions involving many degrees of freedom to obtain the associated free energy changes. The consideration of the variable metric tensor results in well-behaved coordinates that provides good transition state ensembles for the processes under consideration. The application is illustrated with the analysis of an enzymatic reaction studied by means of QM/MM methods.

We critically examine a recently proposed convective replica exchange (cRE) method for enhanced sampling of protein conformation based on theoretical and numerical analysis. The results demonstrate that cRE and related replica exchange with guided annealing (RE-GA) schemes lead to unbalanced exchange attempt probabilities and break detailed balance whenever the system undergoes slow conformational transitions (relative to the temperature diffusion timescale). Nonetheless, numerical simulations suggest that approximate canonical ensembles can be generated for systems with small conformational transition barriers. This suggests that RE-GA maybe suitable for simulating intrinsically disordered proteins, an important class of newly recognized functional proteins. The efficacy of RE-GA is demonstrated by calculating the conformational ensembles of intrinsically disordered kinase inducible domain protein. The results show that RE-GA helps the protein to escape nonspecific compact states more efficiently and provides several fold speedups in generating converged and largely correct ensembles compared to the standard temperature RE. © 2014 Wiley Periodicals, Inc.

Efficiency of temperature replica exchange is severely limited by share cooperative transitions. Previously proposed inclusion of guided annealing cycles can help the system to escape deep energy minima and allow better sampling, but also introduces systematic bias in the simulated ensembles. Nonetheless, the bias is small for disordered protein states. It is demonstrated that replica exchange with simulated annealing (RE-GA) can generate converged and largely correct ensembles of intrinsically disordered proteins with several fold efficiency enhancement.

To promote accuracy of the atom-bond electronegativity equalization method (ABEEMσπ) fluctuating charge polarizable force fields, and extend it to include all transition metal atoms, a new parameter, the reference charge is set up in the expression of the total energy potential function. We select over 700 model molecules most of which model metalloprotein molecules that come from Protein Data Bank. We set reference charges for different apparent valence states of transition metals and calibrate the parameters of reference charges, valence state electronegativities, and valence state hardnesses for ABEEMσπ through linear regression and least square method. These parameters can be used to calculate charge distributions of metalloproteins containing transition metal atoms (Sc-Zn, Y-Cd, and Lu-Hg). Compared the results of ABEEMσπ charge distributions with those obtained by *ab initio* method, the quite good linear correlations of the two kinds of charge distributions are shown. The reason why the STO-3G basis set in Mulliken population analysis for the parameter calibration is specially explained in detail. Furthermore, ABEEMσπ method can also quickly and quite accurately calculate dipole moments of molecules. Molecular dynamics optimizations of five metalloproteins as the examples show that their structures obtained by ABEEMσπ fluctuating charge polarizable force field are very close to the structures optimized by the *ab initio* MP2/6–311G method. This means that the ABEEMσπ/MM can now be applied to molecular dynamics simulations of systems that contain metalloproteins with good accuracy. © 2014 Wiley Periodicals, Inc.

The parameters of reference charges, valence state electronegativities, and valence state hardnesses of atom-bond electronegativity equalization method (ABEEMσπ) are calibrated through linear regression and the least square method. These parameters can be used to calculate charge distributions of metalloproteins containing transition metal atoms (Sc-Zn, Y-Cd, and Lu-Hg). The linear correlations of charge distributions of ABEEMσπ method and *ab initio* method are shown.

Density-functional tight-binding (DFTB) models are computationally efficient approximations to density-functional theory that have been shown to predict reliable structural and energetic properties for various systems. In this work, the reliability and accuracy of the self-consistent-charge DFTB model and its recent extension(s) in predicting the structures, binding energies, charge distributions, and vibrational frequencies of small water clusters containing polyatomic anions of the Hofmeister series (carbonate, sulfate, hydrogen phosphate, acetate, nitrate, perchlorate, and thiocyanate) have been carefully and systematically evaluated on the basis of high-level *ab initio* quantum-chemistry [MP2/aug-cc-pVTZ and CCSD(T)/aug-cc-pVQZ] reference data. Comparison with available experimental data has also been made for further validation. The self-consistent-charge DFTB model, and even more so its recent extensions, are shown to properly account for the structural properties, energetics, intermolecular polarization, and spectral signature of hydrogen-bonding in anionic water clusters at a fraction of the computational cost of *ab initio* quantum-chemistry methods. This makes DFTB models candidates of choice for investigating much larger systems such as seeded water droplets, their structural properties, formation thermodynamics, and infrared spectra. © 2014 Wiley Periodicals, Inc.

The reliability and accuracy of self-consistent-charge density-functional tight-binding (SCC-DFTB) models for describing the structure, energetics, charge distributions, and vibrational frequencies of anionic water clusters have been comprehensively evaluated by comparison of their predictions with results of MP2/aug-cc-pVTZ and CCSD(T)/aug-cc-pVQZ calculations. The SCC-DFTB model is found to perform particularly well, at a fraction of the computational cost, especially when recent corrections for hydrogen bonding and charge transfer are included.

Frozen-density embedding (FDE) is combined with resolution of the identity (RI) Hartree–Fock and a RI-variant of a second-order approximate coupled-cluster singles and doubles (RI-CC2) to determine solvatochromic shifts for the lowest excitation energy of acetone and pyridazine, respectively, each solvated in different environments with total system sizes of about 2.5 nm diameter. The combination of FDE and RI-CC2 increases efficiency and enables the calculation of numerous snapshots with 100 to 300 molecules, also allowing for larger basis sets as well as diffuse functions needed for an accurate treatment of properties. The maximum errors in the solvatochromic shifts amount up to 0.2 eV, which are similar to other approximated studies in the literature. © 2014 Wiley Periodicals, Inc.

Frozen-density embedding is combined with resolution of the identity (RI) Hartree–Fock and a RI-variant of a second-order approximate coupled-cluster singles and doubles (RI-CC2) in the quantum chemistry program KOALA. This enables the calculation of solvatochromic shifts for molecules solvated in different environments with total system sizes of about 2.5 nm diameter without applying molecular mechanics.

A recently developed Thouless-expansion-based diagonalization-free approach for improving the efficiency of self-consistent field (SCF) methods (Noga and Šimunek, J. Chem. Theory Comput. 2010, 6, 2706) has been adapted to the four-component relativistic scheme and implemented within the program package ReSpect. In addition to the implementation, the method has been thoroughly analyzed, particularly with respect to cases for which it is difficult or computationally expensive to find a good initial guess. Based on this analysis, several modifications of the original algorithm, refining its stability and efficiency, are proposed. To demonstrate the robustness and efficiency of the improved algorithm, we present the results of four-component diagonalization-free SCF calculations on several heavy-metal complexes, the largest of which contains more than 80 atoms (about 6000 4-spinor basis functions). The diagonalization-free procedure is about twice as fast as the corresponding diagonalization. © 2014 Wiley Periodicals, Inc.

A recently developed diagonalization-free approach for improving the efficiency of self-consistent field methods has been adapted to four-component relativistic calculations. The method has been thoroughly analyzed and stability and efficiency are improved. The modified algorithm is tested in four-component calculations of several heavy-element complexes.