A detailed first-principle DFT M06/6-311++G(d.p) study of dehydrogenation mechanism of trimeric cluster of lithium amidoborane is presented. The first step of the reaction is association of two LiNH_{2}BH_{3} molecules in the cluster. The dominant feature of the subsequent reaction pathway is activation of H atom of BH_{3} group by three Li atoms with formation of unique Li_{3}H moiety. This Li_{3}H moiety is destroyed prior to dehydrogenation in favor of formation of a triangular Li_{2}H moiety, which interacts with protic H atom of NH_{2} group. As a result of this interaction, Li_{2}H_{2} moiety is produced. It features N^{−}H^{+}H^{−} group suited near the middle plane between two Li^{+} in the transition state that leads to H_{2} release. The transition states of association and hydrogen release steps are similar in energy. It is concluded that the trimer, (LiNH_{2}BH_{3})_{3}, is the smallest cluster that captures the essence of the hydrogen release reaction. © 2016 Wiley Periodicals, Inc.

Cluster of three lithium amidoborane molecules is found to be necessary and sufficient for qualitatively adequate description of thermochemical processes leading to elimination of H_{2}. A detailed investigation of the reaction pathway is presented. Two main steps are found to be similar in energy–association and dehydrogenation. The dominant feature of the pathway prior the dehydrogenation is an activation of H atom of BH_{3} group by three Li atoms with formation of unique Li_{3}H moiety.

An important unsolved problem in molecular and structural biology is the protein folding and structure prediction problem. One major bottleneck for solving this is the lack of an accurate energy to discriminate near-native conformations against other possible conformations. Here we have developed sDFIRE energy function, which is an optimized linear combination of DFIRE (the Distance-scaled Finite Ideal gas Reference state based Energy), the orientation dependent (polar-polar and polar-nonpolar) statistical potentials, and the matching scores between predicted and model structural properties including predicted main-chain torsion angles and solvent accessible surface area. The weights for these scoring terms are optimized by three widely used decoy sets consisting of a total of 134 proteins. Independent tests on CASP8 and CASP9 decoy sets indicate that sDFIRE outperforms other state-of-the-art energy functions in selecting near native structures and in the Pearson's correlation coefficient between the energy score and structural accuracy of the model (measured by TM-score). © 2016 Wiley Periodicals, Inc.

Accurate energy function is needed for predicting protein structure from its sequence. Instead of the sole statistical information, extracted from protein structure database to build an energy-function, a sequence-specific statistical energy function, if formulated, can be more accurate. Thus the statistical potentials with sequence specific matching scores of predicted and model structural properties including predicted main-chain torsion angles and accessible surface area are optimally combined to develop better energy function.

More than 100 naturally occurring modified nucleotides have been found in RNA molecules, in particular in tRNAs. We have determined molecular mechanics force field parameters compatible with the CHARMM36 all-atom additive force field for all these modifications using the CHARMM force field parametrization strategy. Emphasis was placed on fine tuning of the partial atomic charges and torsion angle parameters. Quantum mechanics calculations on model compounds provided the initial set of target data, and extensive molecular dynamics simulations of nucleotides and oligonucleotides in aqueous solutions were used for further refinement against experimental data. The presented parameters will allow for computational studies of a wide range of RNAs containing modified nucleotides, including the ribosome and transfer RNAs. © 2016 Wiley Periodicals, Inc.

All naturally occurring modified ribonucleotides were systematically parametrized in this additive CHARMM force field. This will allow for computational investigation of how specific modifications influence RNA structures, providing insight on structural stability and binding affinity of RNA complexes, such as transfer RNA participating in decoding interactions on the ribosome.

Cuby is a computational chemistry framework written in the Ruby programming language. It provides unified access to a wide range of computational methods by interfacing external software and it implements various protocols that operate on their results. Using structured input files, elementary calculations can be combined into complex workflows. For users, Cuby provides a unified and userfriendly way to automate their work, seamlessly integrating calculations carried out in different computational chemistry programs. For example, the QM/MM module allows combining methods across the interfaced programs and the builtin molecular dynamics engine makes it possible to run a simulation on the resulting potential. For programmers, it provides high-level, object-oriented environment that allows rapid development and testing of new methods and computational protocols. The Cuby framework is available for download at http://cuby4.molecular.cz. © 2016 Wiley Periodicals, Inc.

Cuby is a software framework that provides unified access to a wide range of computational methods by interfacing external software and implements various protocols that operate on their results. Using structured input files, elementary calculations can be combined into complex workflows.

The fast Fourier transform (FFT) sampling algorithm has been used with success in application to protein-protein docking and for protein mapping, the latter docking a variety of small organic molecules for the identification of binding hot spots on the target protein. Here we explore the local rather than global usage of the FFT sampling approach in docking applications. If the global FFT based search yields a near-native cluster of docked structures for a protein complex, then focused resampling of the cluster generally leads to a substantial increase in the number of conformations close to the native structure. In protein mapping, focused resampling of the selected hot spot regions generally reveals further hot spots that, while not as strong as the primary hot spots, also contribute to ligand binding. The detection of additional ligand binding regions is shown by the improved overlap between hot spots and bound ligands. © 2016 Wiley Periodicals, Inc.

The fast Fourier transform (FFT) algorithm enables extremely fast evaluation of energy functions, and hence has been used with great success for protein-protein docking and for the characterization of the binding properties of proteins by docking small probe molecules. While both applications of FFT involve global systematic sampling, the same algorithm can also be used to refine the results by focused resampling on the regions of interest using finer grids or by retaining more structures.

Quantum chemical calculations have been performed at CCSD(T)/def2-TZVP level to investigate the strength and nature of interactions of ammonia (NH_{3}), water (H_{2}O), and benzene (C_{6}H_{6}) with various metal ions and validated with the available experimental results. For all the considered metal ions, a preference for C_{6}H_{6} is observed for dicationic ions whereas the monocationic ions prefer to bind with NH_{3}. Density Functional Theory–Symmetry Adapted Perturbation Theory (DFT-SAPT) analysis has been employed at PBE0AC/def2-TZVP level on these complexes (closed shell), to understand the various energy terms contributing to binding energy (BE). The DFT-SAPT result shows that for the metal ion complexes with H_{2}O electrostatic component is the major contributor to the BE whereas, for C_{6}H_{6} complexes polarization component is dominant, except in the case of alkali metal ion complexes. However, in case of NH_{3} complexes, electrostatic component is dominant for s-block metal ions, whereas, for the d and p-block metal ion complexes both electrostatic and polarization components are important. The geometry (M^{+}–N and M^{+}–O distance for NH_{3} and H_{2}O complexes respectively, and cation–π distance for C_{6}H_{6} complexes) for the alkali and alkaline earth metal ion complexes increases down the group. Natural population analysis performed on NH_{3}, H_{2}O, and C_{6}H_{6} complexes shows that the charge transfer to metal ions is higher in case of C_{6}H_{6} complexes. © 2015 Wiley Periodicals, Inc.

Understanding metal ions with amines, water and aromatic systems is of outstanding importance in biology. An exhaustive computational study has been carried out up to CCSD(T)/def2-TZVP level on a number of main group and transition metal ion interaction with benzene, water and ammonia. Density functional theory based symmetry adapted perturbation theory(DFT-SAPT) analysis has been performed to estimate the contribution of various energy components for the binding energy.

Caryolene formation occur asynchronously in a concerted way through carbocationic rearrangements involving the generation of a secondary or a tertiary carbocation whether the reaction proceeds in the absence or in the presence of NH_{3}, respectively. Both caryolene formation mechanisms are analyzed within the general framework of the reaction force; the reaction force constant is used to gain insights into the synchronicity of the mechanisms and the reaction electronic flux helps to characterize the electronic activity taking place during the reaction. DFT calculations at the B3LYP/6-31+G(d,p) level show a clear difference in the mechanisms of the base promoted or base free caryolene formation reactions. © 2016 Wiley Periodicals, Inc.

Caryolene formation occurs asynchronously in a concerted way through carbocationic rearrangements involving the generation of a secondary or a tertiary carbocation, depending on the absence or in the presence of NH_{3}. Both mechanisms are analyzed within the general framework of the reaction force. The reaction force constant is used to gain insights into the synchronicity of the mechanisms and the reaction electronic flux aids characterization of the electronic activity taking place during reaction.

One of the main challenges in computational protein design (CPD) is the huge size of the protein sequence and conformational space that has to be computationally explored. Recently, we showed that state-of-the-art combinatorial optimization technologies based on Cost Function Network (CFN) processing allow speeding up provable rigid backbone protein design methods by several orders of magnitudes. Building up on this, we improved and injected CFN technology into the well-established CPD package *Osprey* to allow all *Osprey* CPD algorithms to benefit from associated speedups. Because *Osprey* fundamentally relies on the ability of
to produce conformations in increasing order of energy, we defined new
strategies combining CFN lower bounds, with new side-chain positioning-based branching scheme. Beyond the speedups obtained in the new
-CFN combination, this novel branching scheme enables a much faster enumeration of suboptimal sequences, far beyond what is reachable without it. Together with the immediate and important speedups provided by CFN technology, these developments directly benefit to all the algorithms that previously relied on the DEE/
combination inside *Osprey** and make it possible to solve larger CPD problems with provable algorithms. © 2016 Wiley Periodicals, Inc.

Computational protein design (CPD) through Cost Function Networks (CFN) provides important speedups to explore large sequence-conformation spaces and provably identifies the sequence with the conformation of optimal stability (Global Minimum Energy Conformation, GMEC). In addition to quickly finding the GMEC of highly complex protein design problems, CFN-based methods also enable the efficient enumeration of suboptimal solutions. These approaches offer an attractive alternative to the usual CPD methods and were implemented in the well-established CPD package *Osprey*.

The genetic algorithm (GA) is an intelligent approach for finding minima in a highly dimensional parametric space. However, the success of GA searches for low energy conformations of biomolecules is rather limited so far. Herein an improved GA scheme is proposed for the conformational search of oligopeptides. A systematic analysis of the backbone dihedral angles of conformations of amino acids (AAs) and dipeptides is performed. The structural information is used to design a new encoding scheme to improve the efficiency of GA search. Local geometry optimizations based on the energy calculations by the density functional theory are employed to safeguard the quality and reliability of the GA structures. The GA scheme is applied to the conformational searches of Lys, Arg, Met-Gly, Lys-Gly, and Phe-Gly-Gly representative of AAs, dipeptides, and tripeptides with complicated side chains. Comparison with the best literature results shows that the new GA method is both highly efficient and reliable by providing the most complete set of the low energy conformations. Moreover, the computational cost of the GA method increases only moderately with the complexity of the molecule. The GA scheme is valuable for the study of the conformations and properties of oligopeptides. © 2016 Wiley Periodicals, Inc.

The structural information of amino acids and dipeptides is carefully analyzed. An improved GA algorithm with a new encoding strategy utilizing the structural information is proposed. Technical improvements are also made to minimize the possibility of premature convergence of the GA search. Applications to representative amino acids, dipeptides and tripeptide with complicated side chains confirm that the new GA scheme is both efficient and reliable for providing the most complete conformational coverage of the molecules.

SIMPRE is a fortran77 code which uses an effective electrostatic model of point charges to predict the magnetic behavior of rare-earth-based mononuclear complexes. In this article, we present SIMPRE1.2, which now takes into account two further phenomena. First, SIMPRE now considers the hyperfine and quadrupolar interactions within the rare-earth ion, resulting in a more complete and realistic set of energy levels and wave functions. Second, and to widen SIMPRE's predictive capabilities regarding potential molecular spin qubits, it now includes a routine that calculates an upper-bound estimate of the decoherence time considering only the dipolar coupling between the electron spin and the surrounding nuclear spin bath. Additionally, SIMPRE now allows the user to introduce the crystal field parameters manually. Thus, we are able to demonstrate the new features using as examples (i) a Gd-based mononuclear complex known for its properties both as a single ion magnet and as a coherent qubit and (ii) an Er-based mononuclear complex. © 2016 Wiley Periodicals, Inc.

SIMPRE1.2 goes beyond Single Ion Magnet Magnetic Prediction. By considering the coupling between the electronic and the nuclear spins of the lanthanoid ion, it now provides a better description of the low-energy levels. By calculating dipolar interactions, it estimates the quantum decoherence created by the environmental nuclear spins in the crystal. In sum, it is now useful as a tool to provide a first inexpensive description of lanthanoid complexes as molecular spin qubits.

Protein–peptide interactions are essential for all cellular processes including DNA repair, replication, gene-expression, and metabolism. As most protein**–**peptide interactions are uncharacterized, it is cost effective to investigate them computationally as the first step. All existing approaches for predicting protein**–**peptide binding sites, however, are based on protein structures despite the fact that the structures for most proteins are not yet solved. This article proposes the first machine-learning method called SPRINT to make Sequence-based prediction of Protein**–**peptide Residue-level Interactions. SPRINT yields a robust and consistent performance for 10-fold cross validations and independent test. The most important feature is evolution-generated sequence profiles. For the test set (1056 binding and non-binding residues), it yields a Matthews’ Correlation Coefficient of 0.326 with a sensitivity of 64% and a specificity of 68%. This sequence-based technique shows comparable or more accurate than structure-based methods for peptide-binding site prediction. SPRINT is available as an online server at: http://sparks-lab.org/. © 2016 Wiley Periodicals, Inc.

Protein–peptide interactions play vital roles in cellular processes. Experimental determination of protein–peptide interaction, however, is difficult and costly due to peptide flexibility and low binding affinity. Thus, making “educated” computational prediction prior to experimental studies is necessary. All existing computational techniques infer peptide binding sites from protein structures although the structures for the majority of proteins are unknown. Here the first sequence-based method is developed and its accuracy is shown comparable to or better than existing structure-based techniques.

Since the development of structure–activity relationships about 50 years ago, 3D-QSAR methods belong to the most refined ligand-based *in silico* techniques for prediction of biological data using physicochemical molecular fields. In this scenario, this study reports the development and validation of quantum mechanical (QM)-based hydrophobic descriptors derived from the parametrized MST continuum solvation model to be used in 3D-QSAR studies within the framework of the Hydrophobic Pharmacophore (HyPhar) method. To this end, five sets of compounds reported in the literature (dopamine D2/D4 antagonists, antifungal 2-aryl-4-chromanones, and inhibitors of GSK-3, cruzain and thermolysin) have been revisited. The results derived from the QM/MST-based hydrophobic descriptors have been compared with previous CoMFA and CoMSIA studies, and examined in light of the available X-ray crystallographic structures of the targets. The analysis reveals that the combination of electrostatic and nonelectrostatic components of the octanol/water partition coefficient yields pharmacophoric models fully comparable with the predictive potential of standard 3D-QSAR techniques. Moreover, the graphical representation of the hydrophobic maps provides a direct linkage with the pattern of interactions found in crystallographic structures. Overall, the introduction of the QM/MST-based descriptors, which could be easily adapted to other continuum solvation formalisms, paves the way to novel computational strategies for disclosing structure–activity relationships in drug design. © 2016 Wiley Periodicals, Inc.

A novel set of hydrophobic descriptors derived from quantum mechanical-self consistent reaction field IEF/PCM-MST calculations is described within the framework of the hydrophobic pharmacophore (HyPhar) method. The combination of electrostatic and nonelectrostatic components of the octanol/water partition coefficient yields pharmacophoric models fully comparable with the predictive potential of standard 3D-QSAR techniques. HyPhar descriptors provide a novel approach to structure–activity relationships.

Extensive combined quantum mechanical (B3LYP/6-31G*) and molecular mechanical (QM/MM) molecular dynamics simulations have been performed to elucidate the hydrolytic deamination mechanism of cytosine to uracil catalyzed by the yeast cytosine deaminase (yCD). Though cytosine has no direct binding to the zinc center, it reacts with the water molecule coordinated to zinc, and the adjacent conserved Glu64 serves as a general acid/base to shuttle protons from water to cytosine. The overall reaction consists of several proton-transfer processes and nucleophilic attacks. A tetrahedral intermediate adduct of cytosine and water binding to zinc is identified and similar to the crystal structure of yCD with the inhibitor 2-pyrimidinone. The rate-determining step with the barrier of 18.0 kcal/mol in the whole catalytic cycle occurs in the process of uracil departure where the proton transfer from water to Glu64 and nucleophilic attack of the resulting hydroxide anion to C2 of the uracil ring occurs synchronously. © 2016 Wiley Periodicals, Inc.

Yeast cytosine deaminase (yCD) is an enzyme responsible for the activation process of anticancer drugs, and efforts have been put to understand its structure and functions. Computational simulations were performed in order to elucidate how yCD catalyzes the hydrolytic deamination of cytosine to uracil. While the computations show that Glu64 serves as the proton shuttle in various reaction steps, the decisive step was identified as the release of uracil from its trapped state.

Reduction and oxidation (redox) reactions are widely used for removal of nitrocompounds from contaminated soil and water. Structures and redox properties for complexes of nitrocompounds, such as 2,4,6-trinitrotoluene (TNT), 2,4-dinitrotoluene (DNT), 2,4-dinitroanisole (DNAN), and 5-nitro-2,4-dihydro-3*H*−1,2,4-triazol-3-one (NTO), with common inorganic ions (Na^{+}, Cl^{−},
) were investigated at the SMD(Pauling)/PCM(Pauling)/MPWB1K/TZVP level of theory. Atoms in molecules (AIM) theory was applied to analyze the topological properties of the bond critical points involved in the interactions between the nitrocompounds and the ions. Topological analyses show that intermolecular interactions of the types O(N)…Na^{+}, C-H…Cl^{−}(
), and C…Cl^{−}(
) may be discussed as noncovalent closed-shell interactions, while N-H···Cl^{−}(
) hydrogen bonds are partially covalent in nature. Complexation causes significant decrease of redox activity of the nitrocompounds. Analysis of the reduction potentials of the complexes obtained through application of the Pourbaix diagram of an iron/water system revealed that sodium complexes of NTO might be reduced by metallic iron. © 2016 Wiley Periodicals, Inc.

Redox properties of nitrocompounds, such as 2,4,6-trinitrotoluene, 2,4-dinitrotoluene, 2,4-dinitroanisole, and 5-nitro-2,4-dihydro-3*H*-1,2,4-triazol-3-one, are of considerable interest because these compounds may be encountered as groundwater and soil contaminants and redox reactions play a central role in their environmental fate or cleanup under biotic and abiotic conditions. The influence of complexation with common inorganic ions, which can be found in soil and water, on the ability of the nitrocompounds to undergo redox transformations was investigated.

Density functional theory (DFT) calculations with localized as well as plane-wave basis functions are performed for the recently reported dicopper thiolate species Cu_{2}(NGuaS)_{2}Cl_{2} [NGuaS = 2-(1,1,3,3-tetramethylguanidino) benzenethiolate, C_{11}H_{16}N_{3}S] and its bromo derivative [Neuba *et al*., Angew. Chem. Int. Ed. 2012, 51, 1714.]. For both hybrid and semilocal functionals, the neutral complexes are found to have broken symmetry (BS) character, with electron paramagnetic resonance silent, antiferromagnetically coupled [Cu^{2+}…Cu^{2+}] site in which the coupling is driven by super exchange interaction within the Cu_{2}S_{2} diamond core. The accurate theoretical description of the geometric structure, however, provides a major challenge for DFT: (*i*) the multideterminant character of the ground state wave function has to be covered by the BS approach. It requires (*ii*) metageneralized gradient approximations, that is hybrid functionals with an explicit dependence on the kinetic energy of the individual orbitals: In combination with a dispersion correction, the metafunctional TPSSh results in a CuCu distance close to the experimentally observed value of 2.7 Å. For the negative charge state of the complex, a mixed-valent [Cu^{1.5+}…Cu^{1.5+}] electronic structure with a smaller CuCu distance of 2.6 Å is predicted, similar to the value of the Cu_{A} site of cytochrome *c* oxidase. © 2015 Wiley Periodicals, Inc.

Density functional theory calculations for the recently reported dicopper thiolate species Cu_{2}(NGuaS)_{2}Cl_{2} are performed to analyze the magnetic coupling and electronic structure of the Cu_{A}-like Cu_{2}S_{2} diamond core. For both hybrid and semilocal functionals, the neutral complex provides an electronic structure with broken symmetry character. Within the antiferromagnetically coupled [Cu^{2+}…Cu^{2+}] Cu-site, the coupling is mainly driven by super exchange interaction within the Cu_{2}S_{2} diamond core (figure).

Here, an efficient method that predicts natural transition pathways between two endpoint states of an allosteric protein has been proposed. This method helps create structures that bridge these endpoints through multiple iterative and unbiased molecular dynamics simulations with explicit water. Difference distance matrices provide an approach for identifying states involving concerted slow motion. A series of structures are readily generated along the transition pathways of adenylate kinase. Predicted structures may be useful for an initial pathway to evaluate free energy landscapes via umbrella sampling and chain-of-states methods. © 2016 Wiley Periodicals, Inc.

A simple and efficient method that predicts natural transition pathways between two endpoint states of an allosteric protein is proposed. Multiple iterative molecular dynamics simulations guided by different distance matrices provide an approach for identifying states involving concerted slow motion.

We present an algorithm for reducing the computational work involved in coupled-cluster (CC) calculations by sparsifying the amplitude correction within a CC amplitude update procedure. We provide a theoretical justification for this approach, which is based on the convergence theory of inexact Newton iterations. We demonstrate by numerical examples that, in the simplest case of the CCD equations, we can sparsify the amplitude correction by setting, on average, roughly 90% nonzero elements to zeros without a major effect on the convergence of the inexact Newton iterations.

By sparsifying the amplitude correction to approximate solutions to the coupled-cluster amplitude equations, the number of operations in the tensor contraction performed in the inexact Newton algorithm can be significantly reduced. Nearly, the same convergence rate is maintained even when roughly 90% of nonzero elements in the amplitude correction are set to zero (i.e., *z* = 10%).

We report the derivation of approximate analytical nuclear ground-state uncoupled frozen density embedding (FDEu) gradients for the resolution of identity (RI) variant of the second-order approximate coupled cluster singles and doubles (RICC2) as well as density functional theory (DFT), and an efficient implementation thereof in the KOALA program. In order to guarantee a computationally efficient treatment, those gradient terms are neglected which would require the exchange of orbital information. This approach allows for geometry optimizations of single molecules surrounded by numerous molecules with fixed nuclei at RICC2-in-RICC2, RICC2-in-DFT, and DFT-in-DFT FDE level of theory using a dispersion correction, required due to the DFT-based treatment of the interaction in FDE theory. Accuracy and applicability are assessed by the example of two case studies: (a) the Watson-Crick pair adenine-thymine, for which the optimized structures exhibit a maximum error of about 0.08 Å for our best scheme compared to supermolecular reference calculations, (b) carbon monoxide on a magnesium oxide surface model, for which the error amount up to 0.1 Å for our best scheme. Efficiency is demonstrated by successively including environment molecules and comparing to an optimized conventional supermolecular implementation, showing that the method is able to outperform conventional RICC2 schemes already with a rather small number of environment molecules, gaining significant speed up in computation time. © 2016 Wiley Periodicals, Inc.

We report analytical nuclear subsystem gradients for wave-function-based frozen-density embedding (FDE), using density fitting and resolution of the identity methods. The new method allows for efficient geometry optimizations of single molecules surrounded by explicit atomistic surroundings, outperforming conventional RICC2 schemes already for small numbers of environment molecules.

A new Reverse Monte Carlo (RMC) package “fullrmc” for atomic or rigid body and molecular, amorphous, or crystalline materials is presented. fullrmc main purpose is to provide a fully modular, fast and flexible software, thoroughly documented, complex molecules enabled, written in a modern programming language (python, cython, C and C++ when performance is needed) and complying to modern programming practices. fullrmc approach in solving an atomic or molecular structure is different from existing RMC algorithms and software. In a nutshell, traditional RMC methods and software randomly adjust atom positions until the whole system has the greatest consistency with a set of experimental data. In contrast, fullrmc applies smart moves endorsed with reinforcement machine learning to groups of atoms. While fullrmc allows running traditional RMC modeling, the uniqueness of this approach resides in its ability to customize grouping atoms in any convenient way with no additional programming efforts and to apply smart and more physically meaningful moves to the defined groups of atoms. In addition, fullrmc provides a unique way with almost no additional computational cost to recur a group's selection, allowing the system to go out of local minimas by refining a group's position or exploring through and beyond not allowed positions and energy barriers the unrestricted three dimensional space around a group. © 2016 Wiley Periodicals, Inc.

fullrmc is a Reverse Monte Carlo package designed with artificial intelligence to create atomic and molecular models from a set of experimental data and constraints. fullrmc class hierarchy and implementation are quite innovative, allowing easy setup for almost any kind of reverse modeling engine for all sorts of applications. Concepts such as Group, GroupSelector, and MoveGenerator and RMC modeling modes (recurring, refining, and exploring) stand out from all other existing RMC software and packages.

Two fundamental challenges of simulating biologically relevant systems are the rapid calculation of the energy of solvation and the trajectory length of a given simulation. The Generalized Born model with a Simple sWitching function (GBSW) addresses these issues by using an efficient approximation of Poisson–Boltzmann (PB) theory to calculate each solute atom's free energy of solvation, the gradient of this potential, and the subsequent forces of solvation without the need for explicit solvent molecules. This study presents a parallel refactoring of the original GBSW algorithm and its implementation on newly available, low cost graphics chips with thousands of processing cores. Depending on the system size and nonbonded force cutoffs, the new GBSW algorithm offers speed increases of between one and two orders of magnitude over previous implementations while maintaining similar levels of accuracy. We find that much of the algorithm scales linearly with an increase of system size, which makes this water model cost effective for solvating large systems. Additionally, we utilize our GPU-accelerated GBSW model to fold the model system chignolin, and in doing so we demonstrate that these speed enhancements now make accessible folding studies of peptides and potentially small proteins. © 2016 Wiley Periodicals, Inc.

A new algorithm for the Generalized Born model with a Simple sWitching function (GBSW) uses an efficient approximation of the Poisson–Boltzmann theory to accelerate mapping on GPU platforms. Depending on the system size and nonbonded force cutoffs, the new algorithm offers speed increases of 1–2 orders of magnitude over previous implementations while maintaining similar levels of accuracy. The speed enhancements make accessible folding studies of peptides and potentially small proteins.

A method is proposed to obtain coefficients and weights of valence bond (VB) determinants from multi configurational wave functions. This reading of the wave functions can apply to ground states as well as excited states. The method is based on projection operators. Both energetic and overlap-based criteria are used to assess the quality of the resulting VB wave function. The approach gives a simple access to a VB rewriting for low-lying states, and it is applied to the allyl cation, to the allyl radical and to the ethene (notably to the V-state). For these states, large overlap between VB and multi reference wave functions are easily obtained. The approach proves to be useful to propose an interpretation of the nature of the V-state of ethene. © 2015 Wiley Periodicals, Inc.

A bridge was formulated between molecular orbitals and valence bonds wave functions, for both ground and excited states. The approach is shown on calculations that embed multi references and the configuration interaction of singles and double excitations. The overlap is used to assess that the VB description corresponds indeed to the MO's. The cases of allyl (cation or radical) and of the V state of ethene are used.

Protonation pattern strongly affects the properties of molecular systems. To determine protonation equilibria, proton solvation free energy, which is a central quantity in solution chemistry, needs to be known. In this study, proton affinities (PAs), electrostatic energies of solvation, and pK_{A} values were computed in protic and aprotic solvents. The proton solvation energy in acetonitrile (MeCN), methanol (MeOH), water, and dimethyl sulfoxide (DMSO) was determined from computed and measured pK_{A} values for a specially selected set of organic compounds. pK_{A} values were computed with high accuracy using a combination of quantum chemical and electrostatic approaches. Quantum chemical density functional theory computations were performed evaluating PA in the gas-phase. The electrostatic contributions of solvation were computed solving the Poisson equation. The computations yield proton solvation free energies with high accuracy, which are in MeCN, MeOH, water, and DMSO −255.1, −265.9, −266.3, and −266.4 kcal/mol, respectively, where the value for water is close to the consensus value of −265.9 kcal/mol. The pK_{A} values of MeCN, MeOH, and DMSO in water correlates well with the corresponding proton solvation energies in these liquids, indicating that the solvated proton was attached to a single solvent molecule. © 2016 Wiley Periodicals, Inc.

Proton affinities, electrostatic energies of salvation, and pK_{A} values of a reference set of organic molecules are computed combining quantum chemical and electrostatic approaches. Proportional to the free energy of proton dissociation, the pK_{A} calculation is strongly dependent on the free energy of proton solvation. Such energy is here determined with high accuracy in order to obtain the best match between measured and computed pK_{A} values in acetonitrile, methanol, water, and dimethyl sulfoxide.

We introduce an initial implementation of the LICHEM software package. LICHEM can interface with Gaussian, PSI4, NWChem, TINKER, and TINKER–HP to enable QM/MM calculations using multipolar/polarizable force fields. LICHEM extracts forces and energies from unmodified QM and MM software packages to perform geometry optimizations, single-point energy calculations, or Monte Carlo simulations. When the QM and MM regions are connected by covalent bonds, the pseudo-bond approach is employed to smoothly transition between the QM region and the polarizable force field. A series of water clusters and small peptides have been employed to test our initial implementation. The results obtained from these test systems show the capabilities of the new software and highlight the importance of including explicit polarization.

Hybrid QM/MM simulations have become a popular technique in computational chemistry and biology. However, many QM/MM software packages are limited to point-charge based MM potentials. We present a new software package, LICHEM, which performs multipolar and polarizable QM/MM simulations via unmodified QM and MM packages. Our calculations highlight the key features of LICHEM, the importance of including polarization in the MM region, and the polarizable pseudo-bond method.

Although great effort has been made on the transport properties of water molecules through nanometer channels, our understanding on the effect of some basic parameters are still rather poor. In this article, we use molecular dynamics simulations to study the temperature effect on the transport of single-file water molecules through a hydrophobic channel. Of particular interest is that the water flow and average translocation time both exhibit exponential relations with the temperature. Based on the continuous-time random-walk model and Arrhenius equation, we explore some new physical insights on these exponential behaviors. With the increase of temperature, the water dipoles flip more frequently, since the estimated flipping barrier is less than 2 *k*_{B}*T*. Specifically, the flipping frequency also shows an exponential relation with the temperature. Furthermore, the water-water interaction and water occupancy demonstrate linear relations with the temperature, and the water density profiles along the channel axis can be slightly affected by the temperature. These results not only enhance our knowledge about the temperature effect on the single-file water transport, but also have potential implications for the design of controllable nanofluidic machines. © 2016 Wiley Periodicals, Inc.

Molecular dynamics simulations were used to study the temperature effect on the transport of single-file water molecules through a hydrophobic channel. Of particular interest is that the water flow and average translocation time both exhibit exponential relations with temperature.

The competition between hydrogen- and halogen-bonding interactions in complexes of 5-halogenated 1-methyluracil (XmU; X = F, Cl, Br, I, or At) with one or two water molecules in the binding region between C5-X and C4O4 is investigated with M06-2X/6-31+G(d). In the singly-hydrated systems, the water molecule forms a hydrogen bond with C4O4 for all halogens, whereas structures with a halogen bond between the water oxygen and C5-X exist only for X = Br, I, and At. Structures with two waters forming a bridge between C4O and C5-X (through hydrogen- and halogen-bonding interactions) exist for all halogens except F. The absence of a halogen-bonded structure in singly-hydrated ClmU is therefore attributed to the competing hydrogen-bonding interaction with C4O4. The halogen-bond angle in the doubly-hydrated structures (150–160°) is far from the expected linearity of halogen bonds, indicating that significantly non-linear halogen bonds may exist in complex environments with competing interactions. © 2016 Wiley Periodicals, Inc.

Density functional theory calculations reveal competition between halogen- and hydrogen-bonding interactions in complexes of halogenated methyluracil and water.

We simulate the formation of a BN fullerene from an amorphous B cluster at 2000 K by quantum mechanical molecular dynamics based on the density-functional tight-binding method. We run 30 trajectories 200 ps in length, where N atoms are supplied around the target cluster, which is initially an amorphous B_{36} cluster. Most of the incident N atoms are promptly incorporated into the target cluster to form B-N-B bridges or NB_{3} pyramidal local substructures. BN fullerene formation is initiated by alternating BN ring condensation. Spontaneous atomic rearrangement and N_{2} dissociation lead to the construction of an sp^{2} single-shelled structure, during which the BN cluster undergoes a transition from a liquid-like to a solid-like state. Continual atomic rearrangement and sporadic N_{2} dissociation decrease the number of defective rings in the BN cluster and increase the number of six-membered rings, forming a more regular shell structure. The number of four-membered rings tends to remain constant, and contributes to more ordered isolated-tetragon-rule ring placement. © 2016 Wiley Periodicals, Inc.

Rapid formation of BN fullerene from a B_{36} cluster at 2000 K is simulated using the quantum mechanical molecular dynamics based on the density-functional tight-binding method. During the 200 ps simulations, N atoms are periodically supplied around the amorphous B cluster. The supplied N atoms are promptly incorporated into the B cluster. Continual atomic rearrangement of constituent B and N atoms and sporadic N_{2} dissociation lead to the formation of an sp^{2} single-shelled BN cluster.

Carotenoids are important actors both in light-harvesting (LH) and in photoprotection functions of photosynthetic pigment–protein complexes. A deep theoretical investigation of this multiple role is still missing owing to the difficulty of describing the delicate interplay between electronic and nuclear degrees of freedom. A possible strategy is to combine accurate quantum mechanical (QM) methods with classical molecular dynamics. To do this, however, accurate force–fields (FF) are necessary. This article presents a new FF for the different carotenoids present in LH complexes of plants. The results show that all the important structural properties described by the new FF are in very good agreement with QM reference values. This increased accuracy in the simulation of the structural fluctuations is also reflected in the description of excited states. Both the energy order and the different nature of the lowest singlet states are preserved during the dynamics when the new FF is used, whereas an unphysical mixing is found when a standard FF is used. © 2016 Wiley Periodicals, Inc.

An effective strategy is presented to describe the structural effects on electronic excitations of carotenoids by combining specifically parameterized force field and TDDFT calculations. The important structural properties described by the new force field are in very good agreement with quantum mechanical reference values. This increased accuracy in the simulation of the structural fluctuations is also reflected in the description of excited states.

A new computational protocol relying on the use of electrostatic embedding, derived from QM/QM’ ONIOM calculations, to simulate the effect of the crystalline environment on the emission spectra of molecular crystals is here applied to the β-form of salicylidene aniline (SA). The first singlet excited states (*S*_{1}) of the SA cis-keto and trans-keto conformers, surrounded by a cluster of other molecules representing the crystalline structure, were optimized by using a QM/QM’ ONIOM approach with and without electronic embedding. The model system consisting of the central salicylidene aniline molecule was treated at the DFT level by using either the B3LYP, PBE0, or the CAM-B3LYP functional, whereas the real system was treated at the HF level. The CAM-B3LYP/HF level of theory provides emission energies in good agreement with experiment with differences of −20/−32 nm (**cis-keto** form) and −8/−14 nm (**trans-keto** form), respectively, whereas notably larger differences are obtained using global hybrids. Though such differences on the optical properties arise from the density functional choice, the contribution of the electronic embedding is rather independent of the functional used. This plays in favor of a more general applicability of the present protocol to other crystalline molecular systems. © 2015 Wiley Periodicals, Inc.

This study applies a new computational protocol, relying on the use of electrostatic embedding derived from QM/QM’ ONIOM calculations, to simulate the effect of the crystalline environment on the emission spectra of molecular crystals to the β-form of salicylidene aniline.

The number of local minima of the potential energy landscape (PEL) of molecular systems generally grows exponentially with the number of degrees of freedom, so that a crucial property of PEL exploration algorithms is their ability to identify local minima, which are low lying and diverse. In this work, we present a new exploration algorithm, retaining the ability of basin hopping (BH) to identify local minima, and that of *transition based rapidly exploring random trees* (T-RRT) to foster the exploration of yet unexplored regions. This ability is obtained by interleaving calls to the extension procedures of BH and T-RRT, and we show tuning the balance between these two types of calls allows the algorithm to focus on low lying regions. Computational efficiency is obtained using state-of-the art data structures, in particular for searching approximate nearest neighbors in metric spaces. We present results for the BLN69, a protein model whose conformational space has dimension 207 and whose PEL has been studied exhaustively. On this system, we show that the propensity of our algorithm to explore low lying regions of the landscape significantly outperforms those of BH and T-RRT. © 2015 Wiley Periodicals, Inc.

Hybrid is an exploration algorithm combining the abilities of (1) basin-hopping to locate local minima via energy minimization and (2) rapidly growing random trees to explore yet unexplored regions.

Interaction energies between a family of 36 calix[*n*]arenes, their corresponding *thia*- analogues, and two commercially available second generation tyrosine kinase III inhibitors—Bosutinib and Sorafenib—were calculated through DFT methods at the B97D/6-31G(*d*,*p*) level of theory, based on Natural Population Analysis, for the *in silico* development of suitable drug carriers based on the aforementioned macrocycles which can increase their bioavailability and in turn their pharmaceutical efficiency. Molecular Dynamics simulations (production runs: +500 ns) using the General Amber Force Field were also carried out in order to assess the releasing process of these drugs in an explicit aqueous environment. In total, 144 host–guest complexes are examined. According to our results, five-membered SO_{3}H and *i*–Pr functionalized-calixarenes are the best candidates for Sorafenib-carriers while six-membered ones SO_{3}H and C_{2}H_{4}NH_{2} functionalized– are the lead candidates for Bosutinib-carriers. © 2015 Wiley Periodicals, Inc.

Suitable calixarene-based drug delivery agents for Bosutinib and Sorafenib -both used in the treatment of chronic myeloid leukemia- were computationally designed through a mixed QM/DM methodology. The hydrophobic cavity of these macrocycles protect these drugs against non-target binding sites while allowing their release. Interaction energies at the B97D/6-31G(*d,p*) level of theory were calculated and +100 ns molecular dynamics simulations were run in order to assess the drug insertion and release processes.

Computer simulations of molecular systems allow determination of microscopic interactions between individual atoms or groups of atoms, as well as studies of intramolecular motions. Nevertheless, description of structural transformations at the mezoscopic level and identification of causal relations associated with these transformations is very difficult. Structural and functional properties are related to free energy changes. Therefore, to better understand structural and functional properties of molecular systems, it is required to deepen our knowledge of free energy contributions arising from molecular subsystems in the course of structural transformations. The method presented in this work quantifies the energetic contribution of each pair of atoms to the total free energy change along a given collective variable. Next, with the help of a genetic clustering algorithm, the method proposes a division of the system into two groups of atoms referred to *as molecular cogs*. Atoms which cooperate to push the system forward along a collective variable are referred to as forward cogs, and those which work in the opposite direction as reverse cogs. The procedure was tested on several small molecules for which the genetic clustering algorithm successfully found optimal partitionings into molecular cogs. The primary result of the method is a plot depicting the energetic contributions of the identified molecular cogs to the total Potential of Mean Force (PMF) change. Case-studies presented in this work should help better understand the implications of our approach, and were intended to pave the way to a future, publicly available implementation. © 2015 Wiley Periodicals, Inc.

The potential of mean force (PMF) used in studying structural transformations of molecular systems typically does not convey the information which parts of the system propel these transformations. We propose a method of analyzing data from constrained molecular dynamics simulations (cMD) that identifies *molecular cogs*—groups of atoms which push the transformation forward/backward along a collective variable. Contributions of these molecular cogs are then incorporated into a PMF-like graph.

Protein structure prediction is a long-standing problem in molecular biology. Due to lack of an accurate energy function, it is often difficult to know whether the sampling algorithm or the energy function is the most important factor for failure of locating near-native conformations of proteins. This article examines the size dependence of sampling effectiveness by using a perfect “energy function”: the root-mean-squared distance from the target native structure. Using protein targets up to 460 residues from critical assessment of structure prediction techniques (CASP11, 2014), we show that the accuracy of near native structures sampled is relatively independent of protein sizes but strongly depends on the errors of predicted torsion angles. Even with 40% out-of-range angle prediction, 2 Å or less near-native conformation can be sampled. The result supports that the poor energy function is one of the bottlenecks of structure prediction and predicted torsion angles are useful for overcoming the bottleneck by restricting the sampling space in the absence of a perfect energy function. © 2015 Wiley Periodicals, Inc.

The size dependence of sampling effectiveness is examined using the root-mean-squared distance from the target native structure. Using protein targets up to 460 residues from the critical assessment of structure prediction techniques, we show that the accuracy of the sampled near native structures is relatively independent of protein size but strongly depends on errors in the predicted torsion angles. © 2015 Wiley Periodicals, Inc.

Complete active space self-consistent field theory (CASSCF) calculations and subsequent second-order perturbation theory treatment (CASPT2) are discussed in the evaluation of the spin-states energy difference (Δ*H*_{elec}) of a series of seven spin crossover (SCO) compounds. The reference values have been extracted from a combination of experimental measurements and DFT + U calculations, as discussed in a recent article (Vela et al., Phys Chem Chem Phys 2015, 17, 16306). It is definitely proven that the critical IPEA parameter used in CASPT2 calculations of Δ*H*_{elec}, a key parameter in the design of SCO compounds, should be modified with respect to its default value of 0.25 a.u. and increased up to 0.50 a.u. The satisfactory agreement observed previously in the literature might result from an error cancellation originated in the default IPEA, which overestimates the stability of the HS state, and the erroneous atomic orbital basis set contraction of carbon atoms, which stabilizes the LS states. © 2015 Wiley Periodicals, Inc.

The IPEA parameter used within CASPT2 is benchmarked for its use in the calculation of adiabatic energy gaps of Spin Crossover compounds. The importance of the recently discovered error in the ANO-RCC basis set contraction for carbon atoms is also unveiled.

The effect of uniform external electric field on the interactions between small aromatic compounds and an argon atom is investigated using post-HF (MP2, SCS-MP2, and CCSD(T)) and density functional (PBE0-D3, PBE0-TS, and vdW-DF2) methods. The electric field effect is quantified by the difference of interaction energy calculated in the presence and absence of the electric field. All the post-HF methods describe electric field effects accurately although the interaction energy itself is overestimated by MP2. The electric field effect is explained by classical electrostatic models, where the permanent dipole moment from mutual polarization mainly determines its sign. The size of π-conjugated system does not have significant effect on the electric field dependence. We found out that PBE0-based methods give reasonable interaction energies and electric field response in every case, while vdW-DF2 sometimes shows spurious artifact owing to its sensitivity toward the real space electron density. © 2015 Wiley Periodicals, Inc.

The effect of uniform electric field on intermolecular interaction between aromatic molecules (benzene, hexafluorobenzene, and pyrene) and an argon atom are investigated by *ab initio* and DFT methods. We found that the direction of zero-field dipole moment by mutual polarization mainly determines the field effect. The post-HF and PBE0-based methods yield quantitatively correct result, while the vdW-DF2 functional sometimes shows artifacts due to its sensitivity to the quality of real space electron density.

Protein-ligand docking is a commonly used method for lead identification and refinement. While traditional structure-based docking methods represent the receptor as a rigid body, recent developments have been moving toward the inclusion of protein flexibility. Proteins exist in an interconverting ensemble of conformational states, but effectively and efficiently searching the conformational space available to both the receptor and ligand remains a well-appreciated computational challenge. To this end, we have developed the Flexible CDOCKER method as an extension of the family of complete docking solutions available within CHARMM. This method integrates atomically detailed side chain flexibility with grid-based docking methods, maintaining efficiency while allowing the protein and ligand configurations to explore their conformational space simultaneously. This is in contrast to existing approaches that use induced-fit like sampling, such as Glide or Autodock, where the protein or the ligand space is sampled independently in an iterative fashion. Presented here are developments to the CHARMM docking methodology to incorporate receptor flexibility and improvements to the sampling protocol as demonstrated with re-docking trials on a subset of the CCDC/Astex set. These developments within CDOCKER achieve docking accuracy competitive with or exceeding the performance of other widely utilized docking programs. © 2015 Wiley Periodicals, Inc.

Proteins exist in an inter-converting ensemble of conformational states, but effectively and efficiently searching the conformational space available to both the receptor and ligand remains a challenge. Adding receptor flexibility improves protein-ligand docking within the CDOCKER approach. By integrating atomically detailed side chain flexibility with grid-based docking methods, efficiency is maintained while protein and ligand configurations explore conformational space simultaneously.

Dynamic characteristics of protein surfaces are among the factors determining their functional properties, including their potential participation in protein-protein interactions. The presence of clusters of static residues—“stability patches” (SPs)—is a characteristic of protein surfaces involved in intermolecular recognition. The mechanism, by with SPs facilitate molecular recognition, however, remains unclear. Analyzing the surface dynamic properties of the growth hormone and of its high-affinity variant we demonstrated that reshaping of the SPs landscape may be among the factors accountable for the improved affinity of this variant to the receptor. We hypothesized that SPs facilitate molecular recognition by moderating the conformational entropy of the unbound state, diminishing enthalpy–entropy compensation upon binding, and by augmenting the favorable entropy of desolvation. SPs mapping emerges as a valuable tool for investigating the structural basis of the stability of protein complexes and for rationalizing experimental approaches, such as affinity maturation, aimed at improving it. © 2015 Wiley Periodicals, Inc.

Understanding the molecular mechanism of the formation of protein complexes may shed light on the organization and functioning of biological networks, and assist in the structure-based rational design of drugs targeting protein-protein interactions. Protein surfaces constituting the interfaces of protein-protein complexes are characterized by the presence of static areas—“stability patches.” The dynamic properties of protein surfaces are discussed, with particular attention to the presence of interfacial stability patches that may facilitate the formation of protein complexes.

Real-time feedback from iterative electronic structure calculations requires to mediate between the inherently unpredictable execution times of the iterative algorithm used and the necessity to provide data in fixed and short time intervals for real-time rendering. We introduce the concept of a mediator as a component able to deal with infrequent and unpredictable reference data to generate reliable feedback. In the context of real-time quantum chemistry, the mediator takes the form of a surrogate potential that has the same local shape as the first-principles potential and can be evaluated efficiently to deliver atomic forces as real-time feedback. The surrogate potential is updated continuously by electronic structure calculations and guarantees to provide a reliable response to the operator for any molecular structure. To demonstrate the application of iterative electronic structure methods in real-time reactivity exploration, we implement self-consistent semiempirical methods as the data source and apply the surrogate-potential mediator to deliver reliable real-time feedback. © 2015 Wiley Periodicals, Inc.

Interactive reactivity exploration based on iterative electronic structure methods faces an unavoidable incompatibility of unpredictable execution times of such calculations and of the necessity for feedback to be delivered in fixed and short time intervals. This article proposes a mediator strategy involving surrogate potentials to provide real-time feedback that allows for an effective and reliable immersion of a user into the exploration process.

Highly branched polymers such as polyamidoamine (PAMAM) dendrimers are promising macromolecules in the realm of nanobiotechnology due to their high surface coverage of tunable functional groups. Modeling efforts of PAMAM can provide structural and morphological properties, but the inclusion of solvents and the exponential growth of atoms with generations make atomistic simulations computationally expensive. We apply an implicit solvent coarse-grained model, called the Dry Martini force field, to PAMAM dendrimers. The reduced number of particles and the absence of a solvent allow the capture of longer spatiotemporal scales. This study characterizes PAMAM dendrimers of generations one through seven in acidic, neutral, and basic pH environments. Comparison with existing literature, both experimental and theoretical, is done using measurements of the radius of gyration, moment of inertia, radial distributions, and scaling exponents. Additionally, ion coordination distributions are studied to provide insight into the effects of interior and exterior protonation on counter ions. This model serves as a starting point for future designs of larger functionalized dendrimers. © 2015 Wiley Periodicals, Inc.

The implicit solvent Dry Martini coarse-grained model is applied to polyamidoamine (PAMAM) dendrimers. Through size and shape characterizations of generations 1–7 for various pH environments, good agreement is obtained from explicit solvent, and all-atom models, while expending significantly less computational resources. In addition, counter-ion distributions adequately describe the charge distributions of PAMAM caused by different pH environments.

The development of coarse-grained (CG) models for large biomolecules remains a challenge in multiscale simulations, including a rigorous definition of CG representations for them. In this work, we proposed a new stepwise optimization imposed with the boundary-constraint (SOBC) algorithm to construct the CG sites of large biomolecules, based on the s cheme of essential dynamics CG. By means of SOBC, we can rigorously derive the CG representations of biomolecules with less computational cost. The SOBC is particularly efficient for the CG definition of large systems with thousands of residues. The resulted CG sites can be parameterized as a CG model using the normal mode analysis based fluctuation matching method. Through normal mode analysis, the obtained modes of CG model can accurately reflect the functionally related slow motions of biomolecules. The SOBC algorithm can be used for the construction of CG sites of large biomolecules such as F-actin and for the study of mechanical properties of biomaterials. © 2015 Wiley Periodicals, Inc.

The multiscale simulation of biomolecules requires a rigorous definition of their coarse-grained (CG) representation. A stepwise optimization imposed with the boundary-constraint (SOBC) algorithm is developed to construct the CG sties of large biomolecules. The graph shows a four-site CG model of G-actin monomer derived from SOBC.

Excited states of various DNA base dimers and tetramers including Watson-Crick H-bonding and stacking interactions have been investigated by time-dependent density functional theory using nonempirically tuned range-separated exchange (RSE) functionals. Significant improvements are found in the prediction of excitation energies and oscillator strengths, with results comparable to those of high-level coupled-cluster (CC) models (RI-CC2 and EOM-CCSD(T)). The optimally-tuned RSE functional significantly outperforms its non-tuned (default) version and widely-used B3LYP functional. Compared to those high-level CC benchmarks, the large mean absolute deviations of conventional functionals can be attributed to their inappropriate amount of exact exchange and large delocalization errors which can be greatly eliminated by tuning approach. Furthermore, the impacts of H-bonding and *π*-stacking interactions in various DNA dimers and tetramers are analyzed through peak shift of simulated absorption spectra as well as corresponding change of absorption intensity. The result indicates the stacking interaction in DNA tetramers mainly contributes to the hypochromicity effect. The present work provides an efficient theoretical tool for accurate prediction of optical properties and excited states of nucleobase and other biological systems. © 2015 Wiley Periodicals, Inc.

A fundamental understanding of the excited electronic states and photophysical properties of DNA bases and duplex has its great biological importance. In this work, excited states of various DNA base dimers and tetramers including Watson-Crick H-bonding and stacking interactions have been investigated by time-dependent density functional theory (TDDFT), using non-empirically tuned rangeseparated functionals. Their results are comparable to high-level coupled-cluster (CC) methods and significantly outperform their non-tuned version and widely-used B3LYP functional.

The substituent effects on the structures, intermolecular interactions and charge transport properties of a series of corannulene and sumanene derivatives were investigated by DFT method. The intermolecular interaction energy and the potential energy surface of the dimers were also calculated and analyzed in detail, which showed several local energy minima and demonstrated the possible dimer structures in experiment. In addition, the reorganization energy, transfer integral, and carrier mobility were explored to measure the charge transport properties of these substituted corannulenes and sumanenes at different configurations for investigating the substituent effects. Our study is closely related to the experiment and previous theoretical investigation and provides a better understanding of the structure-property relationships for these substituted corannulenes and sumanenes. © 2015 Wiley Periodicals, Inc.

Substituent effects, intermolecular interactions, and charge transport properties of a series of corannulene and sumanene derivatives were investigated by DFT to provide a better understanding of the structure-property relationships for substituted corannulenes and sumanenes. The intermolecular interaction energies and potential energy surfaces of the dimers were also calculated, showing several local energy minimum values and demonstrating possible dimer structures.

The ground-state 4f fine-structure levels in the intrinsic optical transition gaps between the 2p and 5d orbitals of lanthanide sesquioxides (Ln_{2}O_{3}, Ln = La…Lu) were calculated by a two-way crossover search for the *U* parameters for DFT + *U* calculations. The original 4f-shell potential perturbation in the linear response method were reformulated within the constraint volume of the given solids. The band structures were also calculated. This method yields nearly constant optical transition gaps between Ln-5d and O-2p orbitals, with magnitudes of 5.3 to 5.5 eV. This result verifies that the error in the band structure calculations for Ln_{2}O_{3} is dominated by the inaccuracies in the predicted 4f levels in the 2p-5d transition gaps, which strongly and non-linearly depend on the on-site Hubbard *U*. The relationship between the 4f occupancies and Hubbard *U* is non-monotonic and is entirely different from that for materials with 3d or 4d orbitals, such as transition metal oxides. This new linear response DFT + *U* method can provide a simpler understanding of the electronic structure of Ln_{2}O_{3} and enables a quick examination of the electronic structures of lanthanide solids before hybrid functional or GW calculations. © 2015 Wiley Periodicals, Inc.

The ground-state 4f fine-structure levels in the intrinsic optical transition gaps between the 2p and 5d orbitals of lanthanide sesquioxides (Ln_{2}O_{3}, Ln = La…Lu) were calculated by a two-way crossover search for the U parameters for DFT+U calculations. The diagram shows the influence of fully filled and partially filled localized orbitals through local-ranged and nonlocal-ranged perturbations. The difference of the two-way self-consistent output Hubbard *U* converges to zero for fully filled orbitals, while a rigid difference is found between the perturbations of partially filled orbitals due to the local screening of empty components of such orbitals.

Thermodynamic integration (TI) can provide accurate binding free energy insights in a lead optimization program, but its high computational expense has limited its usage. In the effort of developing an efficient and accurate TI protocol for FabI inhibitors lead optimization program, we carefully compared TI with different Amber molecular dynamics (MD) engines (*sander* and *pmemd*), MD simulation lengths, the number of intermediate states and transformation steps, and the Lennard-Jones and Coulomb Softcore potentials parameters in the one-step TI, using eleven benzimidazole inhibitors in complex with *Francisella tularensis* enoyl acyl reductase (FtFabI). To our knowledge, this is the first study to extensively test the new AMBER MD engine, *pmemd*, on TI and compare the parameters of the Softcore potentials in the one-step TI in a protein-ligand binding system. The best performing model, the one-step *pmemd* TI, using 6 intermediate states and 1 ns MD simulations, provides better agreement with experimental results (RMSD = 0.52 kcal/mol) than the best performing implicit solvent method, QM/MM-GBSA from our previous study (RMSD = 3.00 kcal/mol), while maintaining similar efficiency. Briefly, we show the optimized TI protocol to be highly accurate and affordable for the FtFabI system. This approach can be implemented in a larger scale benzimidazole scaffold lead optimization against FtFabI. Lastly, the TI results here also provide structure-activity relationship insights, and suggest the parahalogen in benzimidazole compounds might form a weak halogen bond with FabI, which is a well-known halogen bond favoring enzyme. © 2015 Wiley Periodicals, Inc.

The article highlights the improved thermodynamic integration (TI) approach by using the new Amber molecular dynamics engine, *pmemd*, and the optimized MD simulation lengths, number of intermediate and transition states. The new TI approach is shown to be highly accurate and affordable in the tested system, the bacterial FabI enzyme with benzimidazole inhibitors. The results also provide structure-activity relationship insights and suggest that the para-halogen in benzimidazole compounds form a weak halogen bond with FabI.

As an extension of the Outlier FLOODing (OFLOOD) method [Harada et al., J. Comput. Chem. 2015, 36, 763], the sparsity of the outliers defined by a hierarchical clustering algorithm, FlexDice, was considered to achieve an efficient conformational search as sparsity-weighted “OFLOOD.” In OFLOOD, FlexDice detects areas of sparse distribution as outliers. The outliers are regarded as candidates that have high potential to promote conformational transitions and are employed as initial structures for conformational resampling by restarting molecular dynamics simulations. When detecting outliers, FlexDice defines a rank in the hierarchy for each outlier, which relates to sparsity in the distribution. In this study, we define a lower rank (first ranked), a medium rank (second ranked), and the highest rank (third ranked) outliers, respectively. For instance, the first-ranked outliers are located in a given conformational space away from the clusters (highly sparse distribution), whereas those with the third-ranked outliers are nearby the clusters (a moderately sparse distribution). To achieve the conformational search efficiently, resampling from the outliers with a given rank is performed. As demonstrations, this method was applied to several model systems: Alanine dipeptide, Met-enkephalin, Trp-cage, T4 lysozyme, and glutamine binding protein. In each demonstration, the present method successfully reproduced transitions among metastable states. In particular, the first-ranked OFLOOD highly accelerated the exploration of conformational space by expanding the edges. In contrast, the third-ranked OFLOOD reproduced local transitions among neighboring metastable states intensively. For quantitatively evaluations of sampled snapshots, free energy calculations were performed with a combination of umbrella samplings, providing rigorous landscapes of the biomolecules. © 2015 Wiley Periodicals, Inc.

Biologically rare events play important roles in understanding functions. To computationally reproduce them, Outlier FLOODing (OFLOOD) method is powerful, in which sparse distributions of biological states are detected as outliers and intensively resampled by MD simulations. As an extension, sparsity-weighted OFLOOD method is newly proposed, in which a hierarchical clustering defines ranks of outliers. Accordingly to the ranks, the confirmational resampling from outliers is performed, accerlarating the conformational sampling of bio-molecules.

The UV-induced photochemistry of HCFC-132b (CF_{2}ClCH_{2}Cl) was investigated by computing excited-state properties with time-dependent density functional theory (TDDFT), multiconfigurational second-order perturbation theory (CASPT2), and coupled cluster with singles, doubles, and perturbative triples (CCSD(T)). Excited states calculated with TDDFT show good agreement with CASPT2 and CCSD(T) results, correctly predicting the main excited-states properties. Simulations of ultrafast nonadiabatic dynamics in the gas phase were performed, taking into account 25 electronic states at TDDFT level starting in two different spectral windows (8.5 ± 0.25 and 10.0 ± 0.25 eV). Experimental data measured at 123.6 nm (10 eV) is in very good agreement with our simulations. The excited-state lifetimes are 106 and 191 fs for the 8.5 and 10.0 eV spectral windows, respectively. Internal conversion to the ground state occurred through several different reaction pathways with different products, where 2Cl, C-Cl bond breakage, and HCl are the main photochemical pathways in the low-excitation region, representing 95% of all processes. On the other hand, HCl, HF, and C-Cl bond breakage are the main reaction pathways in the higher excitation region, with 77% of the total yield. © 2015 Wiley Periodicals, Inc.

HCFC-132b is an important industrial compound, with a strong impact on health and environment. Upon UV irradiation, it decomposes into dozens of different photoproducts. In this article, nonadiabatic dynamics simulation is used to explain how photo-decomposition takes place through the competition between diverse reaction pathways in the subpicosecond time scale.

We develop a new method for calculating the hydration free energy (HFE) of a protein with any net charge. The polar part of the energetic component in the HFE is expressed as a linear combination of four geometric measures (GMs) of the protein structure and the generalized Born (GB) energy plus a constant. The other constituents in the HFE are expressed as linear combinations of the four GMs. The coefficients (including the constant) in the linear combinations are determined using the three-dimensional reference interaction site model (3D-RISM) theory applied to sufficiently many protein structures. Once the coefficients are determined, the HFE and its constituents of any other protein structure are obtained simply by calculating the four GMs and GB energy. Our method and the 3D-RISM theory give perfectly correlated results. Nevertheless, the computation time required in our method is over four orders of magnitude shorter.

Although the hydration free energy (HFE) is one of the most important factors in studies on the structural stability of a protein, its calculation is significantly difficult in computational cost and accuracy. We develop a new method for calculating the HFE by combining the generalized Born model and the morphometric approach. Our method gives almost the same result as that from the three-dimensional reference interaction site model (3D-RISM) theory with drastic reduction of computational cost.

A number of model Diels-Alder (D-A) cycloaddition reactions (H_{2}CCH_{2} + cyclopentadiene and H_{2}CCHX + 1,3-butadiene, with X = H, F, CH_{3}, OH, CN, NH_{2}, and NO) were studied by static (transition state - TS and IRC) and dynamics (quasiclassical trajectories) approaches to establish the (a)synchronous character of the concerted mechanism. The use of static criteria, such as the asymmetry of the TS geometry, for classifying and quantifying the (a)synchronicity of the concerted D-A reaction mechanism is shown to be severely limited and to provide contradictory results and conclusions when compared to the dynamics approach. The time elapsed between the events is shown to be a more reliable and unbiased criterion and all the studied D-A reactions, except for the case of H_{2}CCHNO, are classified as synchronous, despite the gradual and quite distinct degrees of (a)symmetry of the TS structures. © 2015 Wiley Periodicals, Inc.

Model Diels-Alder cycloaddition reactions were studied by static and dynamics approaches to establish the (a)synchronous character of the concerted mechanism. The use of static criteria, such as the asymmetry of the TS geometry, for classifying and quantifying the (a)synchronicity of the concerted reaction mechanism provides contradictory results and conclusions when compared to the dynamics approach.

Implicit solvent models for biomolecular simulations have been developed to use in place of more expensive explicit models; however, these models make many assumptions and approximations that are likely to affect accuracy. Here, the changes in free energies of solvation upon folding of several fast folding proteins are calculated from previously run μs–ms simulations with a number of implicit solvent models and compared to the values needed to be consistent with the explicit solvent model used in the simulations. In the majority of cases, there is a significant and substantial difference between the values calculated from the two approaches that is robust to the details of the calculations. These differences could only be remedied by selecting values for the model parameters—the internal dielectric constant for the polar term and the surface tension coefficient for the nonpolar term—that were system-specific or physically unrealistic. We discuss the potential implications of our findings for both implicit and explicit solvent simulations. © 2015 Wiley Periodicals, Inc.

We compare changes in solvation free energy upon folding provided by several implicit solvent models and the TIP3P explicit solvent model. Inconsistencies of an unexpected magnitude were found across the models, which could only be corrected by using settings that were nonphysical or system-specific.

We present a low rank moment expansion of the linear density-density response function. The general interacting (fully nonlocal) density-density response function is calculated by means of its spectral decomposition via an iterative Lanczos diagonalization technique within linear density functional perturbation theory. We derive a unitary transformation in the space of the eigenfunctions yielding subspaces with well-defined moments. This transformation generates the irreducible representations of the density-density response function with respect to rotations within SO(3). This allows to separate the contributions to the electronic response density from different multipole moments of the perturbation. Our representation maximally condenses the physically relevant information of the density-density response function required for intermolecular interactions, yielding a considerable reduction in dimensionality. We illustrate the performance and accuracy of our scheme by computing the electronic response density of a water molecule to a complex interaction potential. © 2015 Wiley Periodicals, Inc.

Intermolecular interactions lead to changes of the electronic charge density. We provide an efficient scheme to express these changes for an arbitrary interaction with an universal yet low-rank tensor. To that extend, we transform the linear density–density response function from its spectral decomposition to a more condensed representation, separating the contributions to the electronic response density from different multipole moments of the perturbation.

The extensibility of force field is a key to solve the missing parameter problem commonly found in force field applications. The extensibility of conventional force fields is traditionally managed in the parameterization procedure, which becomes impractical as the coverage of the force field increases above a threshold. A hierarchical atom-type definition (HAD) scheme is proposed to make extensible atom type definitions, which ensures that the force field developed based on the definitions are extensible. To demonstrate how HAD works and to prepare a foundation for future developments, two general force fields based on AMBER and DFF functional forms are parameterized for common organic molecules. The force field parameters are derived from the same set of quantum mechanical data and experimental liquid data using an automated parameterization tool, and validated by calculating molecular and liquid properties. The hydration free energies are calculated successfully by introducing a polarization scaling factor to the dispersion term between the solvent and solute molecules. © 2015 Wiley Periodicals, Inc.

A hierarchical definition of atom type is proposed to solve the problem of “missing parameters”. The extensible atom type definitions make the force field extensible. Two general force fields are parameterized for some common organic molecules. Parameters are derived from ab initial data and experimental liquid data. Calculation results show good accuracy of the parameters.

Combined quantum mechanical calculations and classical molecular dynamics simulations were conducted to investigate the hydration properties of carboxybetaine zwitterion brushes with varying separation distances between the quaternary ammonium cation and carboxylic anion. The brushes consist of zwitterion trimers and are investigated to mimic interacting zwitterion chains grafted on a substrate as well as polymers with interacting zwitterion side chains. Our results show that the values of both positive and negative charges, their separation distances as well as chain interactions appear to play a critical role in the hydration properties of the zwitterions. The overall hydration property of these zwitterions is dictated by the competition between the strong hydration of the charged groups and the dehydration of the hydrocarbon chains. The strongest hydration occurs when the CH_{2}− unit in the hydrocarbon chain reaches 6–8 for these trimers. Further increase in the hydrocarbon chain length to 10–14 leads to significant and sudden dehydration of the trimers. The water structure and the water residence time surrounding the zwitterions also demonstrate substantial alteration at this length scale. This hydrophilic-to-hydrophobic transition is induced by the hydrophobic interactions of the trimer chains. Our hydration results could explain the observed trend of the superiority of the methylated carbohydrates and poly(ethylene glycol) as antifouling materials compared to corresponding hydroxyl-terminated compounds. © 2015 Wiley Periodicals, Inc.

The average pair distribution functions (*g*(*r*)) correlates the C atoms on the hydrocarbon chains between the cationic and anionic groups and the O atoms in water as a function of the carbon spacer chain length (CSL) on a carboxybetaine trimer. The sudden decrease in the *g*(*r*) function correlates to the hydrophilic-to-hydrophobic transition when the CSL increases from 12 to 14.

A zone-folding (ZF) approach is applied for the estimation of the phonon contributions to thermodynamic properties of carbon-and ZrS_{2}-based nanotubes (NTs) of hexagonal morphology with different chiralities. The results obtained are compared with those from the direct calculation of the thermodynamic properties of NTs using PBE0 hybrid exchange-correlation functional. The phonon contribution to the stability of NTs proved to be negligible for the internal energy and small for the Helmholtz free energy. It is found that the ZF approach allows us an accurate estimation of phonon contributions to internal energy, but slightly overestimates the phonon contributions to entropy. © 2015 Wiley Periodicals, Inc.

In the case of nanotubes rolled up from the layers of layered compounds (such as graphite, ZrS2, or V2O5) the phonon contributions to the heat capacity and internal energy calculated directly and estimated with using the appropriate 2D layer supercell (within the zone-folding approach) remain very close to each other for temperatures up to 600 K.

We investigated the performance of the density functional theory (DFT) functionals PBE, PBE0, M06, and M06-L for describing the molecular and dissociative adsorption of O_{2} onto pure and doped Al(111) surfaces. Adsorption of O_{2} was studied at the perfect Al(111) surface and compared with the case where an additional Al atom was present as an adatom. Additionally, we studied how these functionals perform when different dopants are present at the Al(111) surface in two distinct geometries: as an adatom or as a substitutional atom replacing an Al atom. The performance of the different functionals is greatly affected by the surface geometry. The inclusion of Hartree-Fock exchange in the functional leads to slight differences in adsorption energies for molecular adsorption of O_{2}. These differences become very pronounced for dissociative adsorption, with the hybrids PBE0 and M06 predicting more exergonic adsorption than PBE and M06-L. Furthermore, PBE0 and M06 predicted trends in adsorption energies for defective and perfect surfaces which are in line with the experimental knowledge of the effects of surface defects in adsorption energies. The predictions of the non-hybrids PBE and M06-L point in the opposite direction. The analysis of the contributions of the van der Waals (vdW) forces to the adsorption energies reveals that the PBE and PBE0 functionals have similar difficulties in describing vdW interactions for molecular adsorption of O_{2} while the M06 functional can give a description of these forces with an accuracy which is at least similar to that of the correction of the D3 type. © 2015 Wiley Periodicals, Inc.

Within density functional theory (DFT), different functionals produce very large differences in the description of the molecular and dissociative adsorption of O_{2} at pure and doped aluminum surfaces. These differences are here reported and discussed in view of the type of physical descriptors of the electron density incorporated in each functional.

The free energy calculation library PLUMED has been incorporated into the OpenMM simulation toolkit, with the purpose to perform enhanced sampling MD simulations using the AMOEBA polarizable force field on GPU platform. Two examples, (I) the free energy profile of water pair separation (II) alanine dipeptide dihedral angle free energy surface in explicit solvent, are provided here to demonstrate the accuracy and efficiency of our implementation. The converged free energy profiles could be obtained within an affordable MD simulation time when the AMOEBA polarizable force field is employed. Moreover, the free energy surfaces estimated using the AMOEBA polarizable force field are in agreement with those calculated from experimental data and *ab initio* methods. Hence, the implementation in this work is reliable and would be utilized to study more complicated biological phenomena in both an accurate and efficient way. © 2015 Wiley Periodicals, Inc.

The free energy calculation library PLUMED has been incorporated into the OpenMM simulation toolkit, with the purpose to perform enhanced sampling molecular dynamics simulations using the AMOEBA polarizable force field on GPU platform. Two examples show that the implementation in the work is reliable and would be utilized to study more complicated biological phenomena in both an accurate and efficient way

We investigated by computational means the kinetics and stationary behavior of stochastic dynamics on an ensemble of rough two-dimensional energy landscapes. There are no obvious separations of temporal scales in these systems, which constitute a simple model for the behavior of glasses and some biomaterials. Even though there are significant computational challenges present in these systems due to the large number of metastable states, the Milestoning method is able to compute their kinetic and thermodynamic properties exactly. We observe two clearly distinguished regimes in the overall kinetics: one in which diffusive behavior dominates and another that follows an Arrhenius law (despite the absence of a dominant barrier). We compare our results with those obtained with an exactly-solvable one-dimensional model, and with the results from the rough one-dimensional energy model introduced by Zwanzig. © 2015 Wiley Periodicals, Inc.

We compute, using the Milestoning method, the stationary flux (shown), the mean first passage time of Brownian trajectories, and the free energy (not shown) on a large ensemble of random energy landscapes with varying degrees of roughness and at a wide range of temperatures. We find two different behaviors: a diffusive regime for high temperatures and an Arrhenius-like regime for low temperatures.

Intrinsically disordered regions of proteins can gain structure by binding to a partner. This process, of coupled folding and binding (CFaB), is a fundamental part of many important biological processes. Structure-based models have proven themselves capable of revealing fundamental aspects of how CFaB occurs, however, typical methods to enhance the sampling of these transitions, such as replica exchange, do not adequately sample the transition state region of this extremely rare process. Here, we use a variant of Umbrella Sampling to enforce sampling of the transition states of CFaB of HdeA monomers at neutral pH, an extremely rare process that occurs over timescales ranging from seconds to hours. Using high resolution sampling in the transition state region, we cluster states along the principal transition path to obtain a detailed description of coupled binding and folding for the HdeA dimer, revealing new insight into the ensemble of states that are accessible to client recognition. We then demonstrate that exchanges between umbrella sampling windows, as done in previous work, significantly improve relaxation in variables orthogonal to the restraints used. Altogether, these results show that Window-Exchange Umbrella Sampling is a promising approach for systems that exhibit flexible binding, and can reveal transition state ensembles of these systems in high detail. © 2015 Wiley Periodicals, Inc.

Intrinsically disordered proteins often fold in conjunction with binding to their partner. Sampling configurations corresponding to the transition between unfolded and bound conformational ensembles presents a complex sampling problem. A two-dimensional sampling method, Window-Exchange Umbrella Sampling using contact fractions, is developed to address this issue.

Self-guided Langevin dynamics (SGLD) is a molecular simulation method that enhances conformational search and sampling via acceleration of the low frequency motions of the system. This acceleration is produced via introduction of a guiding force which breaks down the detailed-balance property of the dynamics, implying that some reweighting is necessary to perform equilibrium sampling. Here, we eliminate the need of reweighing and show that the *NVT* and *NPT* ensembles are sampled exactly by a new version of self-guided motion involving a generalized Langevin equation (GLE) in which the random force is modified so as to restore detailed-balance. Through the examples of alanine dipeptide and argon liquid, we show that this SGLD-GLE method has enhanced conformational sampling capabilities compared with regular Langevin dynamics (LD) while being of comparable computational complexity. In particular, SGLD-GLE is fully size extensive and can be used in arbitrarily large systems, making it an appealing alternative to LD. © 2015 Wiley Periodicals, Inc.

Self-guided Langevin dynamics (SGLD) is a molecular simulation method that enhances conformational search and sampling via acceleration of the low frequency motions of the molecular system. To eliminate the need of reweighting, the SGLD-generalized Langevin equation (GLE) method is proposed, which samples exact ensemble distribution and has enhanced conformational sampling. Using an alanine dipeptide and liquid argon, SGLD-GLE can produce correct *NVT* and *NPT* ensemble distributions while achieving enhanced conformational sampling.

The atomic mechanisms of isomerization of ATP-Mg^{2+} in solution are characterized using the recently developed String Method with Optimal Molecular Alignment (SOMA) and molecular-dynamics simulations. Bias-Exchange Metadynamics simulations are first performed to identify the primary conformers of the ATP-Mg^{2+} complex and their connectivity. SOMA is then used to elucidate the minimum free-energy path (MFEP) for each transition, in a 48-dimensional space. Analysis of the per-atom contributions to the global free-energy profiles reveals that the mechanism of these transitions is controlled by the Mg^{2+} ion and its coordinating oxygen atoms in the triphosphate moiety, as well as by the ion-hydration shell. Metadynamics simulations in path collective variables based on the MFEP demonstrate these isomerizations proceed across a narrow channel of configurational space, thus validating the premise underlying SOMA. This study provides a roadmap for the examination of conformational changes in biomolecules, based on complementary enhanced-sampling techniques with different strengths. © 2015 Wiley Periodicals, Inc.

The mechanisms of isomerization of ATP-Mg^{2+} in solution are examined with three complementary enhanced-sampling simulation methods. The recently developed String Method with Optimal Molecular Alignment is used to identify and characterize the minimum free-energy paths for the major conformational transitions of the complex, in a 48-dimensional space. This analysis reveals the driving forces controlling these isomerization mechanisms at single-atom resolution.

Hydrogen sulfide (H_{2}S), a commonly known toxic gas compound, possesses unique chemical features that allow this small solute molecule to quickly diffuse through cell membranes. Taking advantage of the recent orthogonal space tempering (OST) method, we comparatively mapped the transmembrane free energy landscapes of H_{2}S and its structural analogue, water (H_{2}O), seeking to decipher the molecular determinants that govern their drastically different permeabilities. As revealed by our OST sampling results, in contrast to the highly polar water solute, hydrogen sulfide is evidently amphipathic, and thus inside membrane is favorably localized at the interfacial region, that is, the interface between the polar head-group and nonpolar acyl chain regions. Because the membrane binding affinity of H_{2}S is mainly governed by its small hydrophobic moiety and the barrier height inbetween the interfacial region and the membrane center is largely determined by its moderate polarity, the transmembrane free energy barriers to encounter by this toxic molecule are very small. Moreover when H_{2}S diffuses from the bulk solution to the membrane center, the above two effects nearly cancel each other, so as to lead to a negligible free energy difference. This study not only explains why H_{2}S can quickly pass through cell membranes but also provides a practical illustration on how to use the OST free energy sampling method to conveniently analyze complex molecular processes. © 2015 Wiley Periodicals, Inc.

The orthogonal space tempering simulation shows that hydrogen sulfide is amphipathic, and thus is favorably localized at the interface between the head-group and acyl chain regions. Because the membrane binding affinity of H_{2}S is mainly governed by its small hydrophobic moiety and the barrier height inbetween the interfacial region and the membrane center is largely determined by its moderate polarity, the trans-membrane free energy barriers to encounter by this toxic molecule are very small.

Mark S. Gordon and co-workers have observed a new type of reaction pathway that involves a nontotally symmetric trifurcation. On page 487 (DOI: 10.1002/jcc.24241), the pathway is investigated for a typical SN2 reaction and the branching mechanism is discussed based on the reaction path curvature and net atomic charges. Furthermore, the possibility of a nonotally symmetric *n*-furcation is discussed.

Electrostatics is often considered to be the main driving force for complexation in supramolecular frameworks. In the study of large systems under periodic boundary conditions, the evaluation of electrostatic energy benefits from the SPME algorithm. On page 494 (DOI: 10.1002/jcc.24257), Pengyu Y. Ren, Jean-Philip Piquemal, and co-workers discuss a QM inspired correction to handle charge penetration in a variety of systems, including cations, is incorporated into the SPME framework.

When an electric field is applied to an insulating membrane, movement of charged particles through a nanopore is induced. The measured ionic current reports on biomolecules passing through the nanopore. In this work, we explored the kinetics of DNA unzipping in a nanopore using our coarse-grained model (Stachiewicz and Molski, J. Comput. Chem. 2015, 36, 947). Coarse graining allowed a more detailed analysis for a wider range of parameters than all-atom simulations. Dependence of the translocation mode (unzipping or distortion) on the pore diameter was examined, and the threshold voltages were estimated. We determined the potential of mean force, position-dependent diffusion coefficient, and position-dependent effective charge for the DNA unzipping. The three molecular profiles were correlated with the ionic current and molecular events. On the unzipping/translocation force profile, two energy maxima were found, one of them corresponding to the unzipping, and the other to the translocation barriers. The unzipping kinetics were further explored using Brownian dynamics. © 2015 Wiley Periodicals, Inc.

When an electric field is applied to an insulating membrane, movement of charged particles through a nanopore is induced. In this work, the kinetics of DNA unzipping in a nanopore is explored using a coarse-grained model. Dependence of the translocation mode on the pore diameter is examined, and the threshold voltages are estimated. The potential of mean force, position-dependent diffusion coefficient and position-dependent effective charge are determined for the DNA unzipping.

The restricted active-space (RAS) approach can accurately simulate metal L-edge X-ray absorption spectra of first-row transition metal complexes without the use of any fitting parameters. These characteristics provide a unique capability to identify unknown chemical species and to analyze their electronic structure. To find the best balance between cost and accuracy, the sensitivity of the simulated spectra with respect to the method variables has been tested for two models, [FeCl_{6}]^{3–} and [Fe(CN)_{6}]^{3–}. For these systems, the reference calculations give deviations, when compared with experiment, of ≤1 eV in peak positions, ≤30% for the relative intensity of major peaks, and ≤50% for minor peaks. When compared with these deviations, the simulated spectra are sensitive to the number of final states, the inclusion of dynamical correlation, and the ionization potential electron affinity shift, in addition to the selection of the active space. The spectra are less sensitive to the quality of the basis set and even a double-*ζ* basis gives reasonable results. The inclusion of dynamical correlation through second-order perturbation theory can be done efficiently using the state-specific formalism without correlating the core orbitals. Although these observations are not directly transferable to other systems, they can, together with a cost analysis, aid in the design of RAS models and help to extend the use of this powerful approach to a wider range of transition metal systems. © 2015 Wiley Periodicals, Inc.

With an appropriate choice of active space, basis set, and computational procedure, the restricted active space approach can be used to simulate metal L-edge X-ray absorption spectra with reasonable accuracy and computational cost. The sensitivity of the simulated results with respect to geometrical changes opens up for analysis of dynamical processes.

A new type of reaction pathway which involves a nontotally symmetric trifurcation was found and investigated for a typical S_{N}2-type reaction, NC^{-} + CH_{3}X NCCH_{3} + X^{-} (X = F, Cl). A nontotally symmetric valley-ridge inflection (VRI) point was located along the *C*_{3}_{v} reaction path. For X = F, the minimum energy path (MEP) starting from the transition state (TS) leads to a second-order saddle point with *C*_{3}_{v} symmetry, which connects three product minima of *C _{s}* symmetry. For X = Cl, four product minima have been observed, of which three belong to

A new type of reaction pathway which involves a nontotally symmetric trifurcation was found and investigated for the S_{N}2-type reaction, NC^{-} + CH_{3}X NCCH_{3} + X^{-} (X = F, Cl). A nontotally symmetric valley-ridge inflection (VRI) point was located along the *C*_{3}_{v} reaction path. The branching path from the VRI point to the lower symmetry minima was determined. The possibility of a nontotally symmetric *n-furcation* is discussed.

We propose a general coupling of the Smooth Particle Mesh Ewald SPME approach for distributed multipoles to a short-range charge penetration correction modifying the charge-charge, charge-dipole and charge-quadrupole energies. Such an approach significantly improves electrostatics when compared to *ab initio* values and has been calibrated on Symmetry-Adapted Perturbation Theory reference data. Various neutral molecular dimers have been tested and results on the complexes of mono- and divalent cations with a water ligand are also provided. Transferability of the correction is adressed in the context of the implementation of the AMOEBA and SIBFA polarizable force fields in the TINKER-HP software. As the choices of the multipolar distribution are discussed, conclusions are drawn for the future penetration-corrected polarizable force fields highlighting the mandatory need of non-spurious procedures for the obtention of well balanced and physically meaningful distributed moments. Finally, scalability and parallelism of the short-range corrected SPME approach are addressed, demonstrating that the damping function is computationally affordable and accurate for molecular dynamics simulations of complex bio- or bioinorganic systems in periodic boundary conditions. © 2016 Wiley Periodicals, Inc.

A general and scalable penetration correction has been implemented for distributed multipole electrostatics into Tinker to be used in conjunction to the smooth particle Mesh Ewald approach for periodic boundary conditions simulations with polarizable force fields such as AMOEBA and SIBFA.

In this report, we summarize and describe the recent unique updates and additions to the Molcas quantum chemistry program suite as contained in release version 8. These updates include natural and spin orbitals for studies of magnetic properties, local and linear scaling methods for the Douglas–Kroll–Hess transformation, the generalized active space concept in MCSCF methods, a combination of multiconfigurational wave functions with density functional theory in the MC-PDFT method, additional methods for computation of magnetic properties, methods for diabatization, analytical gradients of state average complete active space SCF in association with density fitting, methods for constrained fragment optimization, large-scale parallel multireference configuration interaction including analytic gradients via the interface to the Columbus package, and approximations of the CASPT2 method to be used for computations of large systems. In addition, the report includes the description of a computational machinery for nonlinear optical spectroscopy through an interface to the QM/MM package Cobramm. Further, a module to run molecular dynamics simulations is added, two surface hopping algorithms are included to enable nonadiabatic calculations, and the DQ method for diabatization is added. Finally, we report on the subject of improvements with respects to alternative file options and parallelization. © 2015 Wiley Periodicals, Inc.

The Molcas quantum chemistry program package has a long history, and with the release of Molcas 8 in 2014, it continues to offer state-of-the-art tools for computational chemistry. This article summarizes some of the most significant additions and improvements included in the package in the last 6 years. There are sections on electron correlation methods, relativistic features, molecular dynamics, gradients and optimizations, and technical features.