Journal of Computational Chemistry

A simulation strategy for the atomistic modeling of flexible molecules covalently tethered to rigid surfaces: Application to peptides.

Publication Date: 2010 Aug 30 PMID: 20806264
Authors: Curco, D. - Zanuy, D. - Nussinov, R. - Aleman, C.
Journal: J Comput Chem

A computational strategy to model flexible molecules tethered to a rigid inert surface is presented. The strategy is able to provide uncorrelated relaxed microstructures at the atomistic level. It combines an algorithm to generate molecules tethered to the surface without atomic overlaps, a method to insert solvent molecules and ions in the simulation box, and a powerful relaxation procedure. The reliability of the strategy has been investigated by simulating two different systems: (i) mixed monolayers consisting of binary mixtures of long-chain alkyl thiols of different lengths adsorbed on a rigid inert surface and (ii) CREKA (Cys-Arg-Glu-Lys-Ala), a short linear pentapeptide that recognizes clotted plasma proteins and selectively homes to tumors, covalently tethered to a rigid inert surface in aqueous solution. In the first, we examined the segregation of the two species in the monolayers using different long-chain:short-chain ratios, whereas in the second, we explored the conformational space of CREKA and ions distribution considering densities of peptides per nm(2) ranging from 0.03 to 1.67. Results indicate a spontaneous segregation in alkyl thiol monolayers, which enhances when the concentration of longest chains increases. However, the whole conformational profile of CREKA depends on the number of molecules tethered to the surface pointing out the large influence of molecular density on the intermolecular interactions, even though the bioactive conformation was found as the most stable in all cases. (c) 2010 Wiley Periodicals, Inc. J Comput Chem, 2010.

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CABS-NMR-De novo tool for rapid global fold determination from chemical shifts, residual dipolar couplings and sparse methyl-methyl noes.

Publication Date: 2010 Aug 30 PMID: 20806263
Authors: Latek, D. - Kolinski, A.
Journal: J Comput Chem

Recent development of nuclear magnetic resonance (NMR) techniques provided new types of structural restraints that can be successfully used in fast and low-cost global protein fold determination. Here, we present CABS-NMR, an efficient protein modeling tool, which takes advantage of such structural restraints. The restraints are converted from original NMR data to fit the coarse grained protein representation of the C-Alpha-Beta-Side-group (CABS) algorithm. CABS is a Monte Carlo search algorithm that uses a knowledge-based force field. Its versatile structure enables a variety of protein-modeling protocols, including purely de novo folding, folding guided by restraints derived from template structures or, structure assembly based on experimental data. In particular, CABS-NMR uses the distance and angular restraints set derived from various NMR experiments. This new modeling technique was successfully tested in structure determination of 10 globular proteins of size up to 216 residues, for which sparse NMR data were available. Additional detailed analysis was performed for a S100A1 protein. Namely, we successfully predicted Nuclear Overhauser Effect signals on the basis of low-energy structures obtained from chemical shifts by CABS-NMR. It has been observed that utility of chemical shifts and other types of experimental data (i.e. residual dipolar couplings and methyl-methyl Nuclear Overhauser Effect signals) in the presented modeling pipeline depends mainly on size of a protein and complexity of its topology. In this work, we have provided tools for either post-experiment processing of various kinds of NMR data or fast and low-cost structural analysis in the still challenging field of new fold predictions. (c) 2010 Wiley Periodicals, Inc. J Comput Chem, 2010.

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Artificial neural network-based drug design for diabetes mellitus using flavonoids.

Publication Date: 2010 Aug 30 PMID: 20806262
Authors: Patra, J. C. - Chua, B. H.
Journal: J Comput Chem

Diabetes mellitus is a chronic metabolic disease involving the failure to regulate glucose blood levels in the body and has been linked with numerous detrimental complications. Studies have shown that these complications can be linked to the activities of aldose reductase (AR), an enzyme of the polyol pathway. Flavonoids have been identified as good AR inhibitors (ARIs) and are also strong antioxidants with radical scavenging (RS) activity. As such, flavonoids show potential to become a better class of ARIs because they are able to concurrently address the oxidative stress issue. In this article, we carried out quantitative structure-activity relationship analysis of flavones and flavonols (members of flavonoid family) using artificial neural networks. Three computer experiments were conducted to study the influence of hydrogen (H), hydroxyl (--OH), and methoxyl (--CH(3)) functional groups on eight substitution sites of the lead flavone molecule and to predict potential ARIs. Of 6561 possible flavones and flavonols, in experiment 1, we predicted 69 potent ARIs, and in experiment 2, we predicted 346 compounds with strong RS activity. In experiment 3, we combined these results to find overlapping compounds with both strong AR inhibition and RS activity and we are able to predict 10 potent compounds with strong AR inhibition (IC(50) < 0.3 muM) and RS activity (IC(25) < 1.0 muM). These 10 compounds show promise of being good therapeutic agents in the prevention of diabetic complications and is suggested to undergo further wet bench experimentation to prove their potency. (c) 2010 Wiley Periodicals, Inc. J Comput Chem, 2010.

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Intramolecular interactions of L-phenylalanine: Valence ionization spectra and orbital momentum distributions of its fragment molecules.

Publication Date: 2010 Aug 30 PMID: 20806261
Authors: Ganesan, A. - Wang, F. - Falzon, C.
Journal: J Comput Chem

Intramolecular interactions between fragments of L-phenylalanine, i.e., phenyl and alaninyl, have been investigated using dual space analysis (DSA) quantum mechanically. Valence space photoelectron spectra (PES), orbital energy topology and correlation diagram, as well as orbital momentum distributions (MDs) of L-phenylalanine, benzene and L-alanine are studied using density functional theory methods. While fully resolved experimental PES of L-phenylalanine is not yet available, our simulated PES reproduces major features of the experimental measurement. For benzene, the simulated orbital MDs for 1e(1g) and 1a(2u) orbitals also agree well with those measured using electron momentum spectra. Our theoretical models are then applied to reveal intramolecular interactions of the species on an orbital base, using DSA. Valence orbitals of L-phenylalanine can be essentially deduced into contributions from its fragments such as phenyl and alaninyl as well as their interactions. The fragment orbitals inherit properties of their parent species in energy and shape (ie., MDs). Phenylalanine orbitals show strong bonding in the energy range of 14-20 eV, rather than outside of this region. This study presents a competent orbital based fragments-in-molecules picture in the valence space, which supports the fragment molecular orbital picture and building block principle in valence space. The optimized structures of the molecules are represented using the recently developed interactive 3D-PDF technique. (c) 2010 Wiley Periodicals, Inc. J Comput Chem, 2010.

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Performance of 3D-space-based atoms-in-molecules methods for electronic delocalization aromaticity indices.

Publication Date: 2010 Aug 27 PMID: 20803487
Authors: Heyndrickx, W. - Salvador, P. - Bultinck, P. - Sola, M. - Matito, E.
Journal: J Comput Chem

Several definitions of an atom in a molecule (AIM) in three-dimensional (3D) space, including both fuzzy and disjoint domains, are used to calculate electron sharing indices (ESI) and related electronic aromaticity measures, namely, I(ring) and multicenter indices (MCI), for a wide set of cyclic planar aromatic and nonaromatic molecules of different ring size. The results obtained using the recent iterative Hirshfeld scheme are compared with those derived from the classical Hirshfeld method and from Bader's quantum theory of atoms in molecules. For bonded atoms, all methods yield ESI values in very good agreement, especially for C-C interactions. In the case of nonbonded interactions, there are relevant deviations, particularly between fuzzy and QTAIM schemes. These discrepancies directly translate into significant differences in the values and the trends of the aromaticity indices. In particular, the chemically expected trends are more consistently found when using disjoint domains. Careful examination of the underlying effects reveals the different reasons why the aromaticity indices investigated give the expected results for binary divisions of 3D space. (c) 2010 Wiley Periodicals, Inc. J Comput Chem, 2010.

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Time-dependent density functional theory study on the absorption spectrum of Coumarin 102 and its hydrogen-bonded complexes.

Publication Date: 2010 Aug 27 PMID: 20803485
Authors: Zhao, W. - Ding, Y. - Xia, Q.
Journal: J Comput Chem

The effect of both solvent polarity and hydrogen bonding (HB) on the electronic transition energy of Coumarin 102 (C102) has been examined using the time-dependent density functional theory (TDDFT). Solvent effect on both geometry and electronic transition energy is evaluated using the polarizable continuum model (PCM). A linear relation of the absorption maximum of C102 with the solvent polarity function Deltaf is found using the TDDFT-PCM method for all solvents except dimethyl sulfoxide. The solvent polarity and the type B HB between the carbonyl oxygen and solvent hydrogen atom make the absorption wavelength redshift, whereas the type A HB between the amino nitrogen atom and solvent hydrogen atom has an opposite effect on the absorption wavelength. The calculated absorption wavelengths of C102 with two type B HB between the carbonyl oxygen and solvent hydrogen atom are in excellent agreement with experimental measurements. The solvatochromism of C102 is analyzed in terms of the Kamlet-Taft equation and the parameters s and a are discussed. (c) 2010 Wiley Periodicals, Inc. J Comput Chem, 2010.

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Rapid sampling of all-atom peptides using a library-based polymer-growth approach.

Publication Date: 2010 Aug 23 PMID: 20734315
Authors: Mamonov, A. B. - Zhang, X. - Zuckerman, D. M.
Journal: J Comput Chem

We adapted existing polymer growth strategies for equilibrium sampling of peptides described by modern atomistic forcefields with a simple uniform dielectric solvent. The main novel feature of our approach is the use of precalculated statistical libraries of molecular fragments. A molecule is sampled by combining fragment configurations-of single residues in this study-which are stored in the libraries. Ensembles generated from the independent libraries are reweighted to conform with the Boltzmann-factor distribution of the forcefield describing the full molecule. In this way, high-quality equilibrium sampling of small peptides (4-8 residues) typically requires less than one hour of single-processor wallclock time and can be significantly faster than Langevin simulations. Furthermore, approximate, clash-free ensembles can be generated for larger peptides (up to 32 residues in this study) in less than a minute of single-processor computing. We discuss possible applications of our growth procedure to free energy calculation, fragment assembly protein-structure prediction protocols, and to "multi-resolution" sampling. (c) 2010 Wiley Periodicals, Inc. J Comput Chem, 2010.

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Characterizing amyloid-beta protein misfolding from molecular dynamics simulations with explicit water.

Publication Date: 2010 Aug 23 PMID: 20734314
Authors: Lee, C. - Ham, S.
Journal: J Comput Chem

Extracellular deposition of amyloid-beta (Abeta) protein, a fragment of membrane glycoprotein called beta-amyloid precursor transmembrane protein (betaAPP), is the major characteristic for the Alzheimer's disease (AD). However, the structural and mechanistic information of forming Abeta protein aggregates in a lag phase in cell exterior has been still limited. Here, we have performed multiple all-atom molecular dynamics simulations for physiological 42-residue amyloid-beta protein (Abeta42) in explicit water to characterize most plausible aggregation-prone structure (APS) for the monomer and the very early conformational transitions for Abeta42 protein misfolding process in a lag phase. Monitoring the early sequential conformational transitions of Abeta42 misfolding in water, the APS for Abeta42 monomer is characterized by the observed correlation between the nonlocal backbone H-bond formation and the hydrophobic side-chain exposure. Characteristics on the nature of the APS of Abeta42 allow us to provide new insight into the higher aggregation propensity of Abeta42 over Abeta40, which is in agreement with the experiments. On the basis of the structural features of APS, we propose a plausible aggregation mechanism from APS of Abeta42 to form fibril. The structural and mechanistic observations based on these simulations agree with the recent NMR experiments and provide the driving force and structural origin for the Abeta42 aggregation process to cause AD. (c) 2010 Wiley Periodicals, Inc. J Comput Chem, 2010.

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Quality of random number generators significantly affects results of Monte Carlo simulations for organic and biological systems.

Publication Date: 2010 Aug 23 PMID: 20734313
Authors: Click, T. H. - Liu, A. - Kaminski, G. A.
Journal: J Comput Chem

We have simulated pure liquid butane, methanol, and hydrated alanine polypeptide with the Monte Carlo technique using three kinds of random number generators (RNG's)-the standard Linear Congruential Generator (LCG), a modification of the LCG with additional randomization used in the BOSS software, and the "Mersenne Twister" generator by Matsumoto and Nishimura. While using the latter two RNG's leads to reasonably similar physical features, the LCG produces significant different results. For the pure fluids, a noticeable expansion occurs. Using the original LCG on butane yields, a molecular volume of 171.4 A(3) per molecule compared to about 163.6-163.9 A(3) for the other two generators, a deviation of about 5%. For methanol, the LCG produces an average volume of 86.3 A(3) per molecule, which is about 24% higher than the 68.8-70.2 A(3) obtained with the RNG's in BOSS and the generator by Matsumoto and Nishimura. In case of the hydrated tridecaalanine peptide, the volume and energy tend to be noticeably greater with the LCG than with the BOSS (modified LCG) RNG's. For the simulated hydrated extended conformation of tridecaalanine, the difference in volume reached about 87%. The uniformity and periodicity of the generators do not seem to play the crucial role in these phenomena. We conclude that, it is important to test a RNG's by modeling a system such as the pure liquid methanol with a well-established force field before routinely employing it in Monte Carlo simulations. (c) 2010 Wiley Periodicals, Inc. J Comput Chem, 2010.

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Discovery of new beta-D-galactosidase inhibitors via pharmacophore modeling and QSAR analysis followed by in silico screening.

Publication Date: 2010 Aug 20 PMID: 20730780
Authors: Abdula, A. M. - Khalaf, R. A. - Mubarak, M. S. - Taha, M. O.
Journal: J Comput Chem

Glycosidases, including beta-D-galactosidase, are involved in a variety of metabolic disorders, such as diabetes, viral or bacterial infections, and cancer. Accordingly, we were prompted to find new beta-D-galactosidase inhibitors. Towards this end, we scanned the pharmacophoric space of this enzyme using a set of 41 known inhibitors. Genetic algorithm and multiple linear regression analyses were used to select an optimal combination of pharmacophoric models and physicochemical descriptors to yield self-consistent and predictive quantitative structure-activity relationship (QSAR). Five pharmacophores emerged in the QSAR equations suggesting the existence of more than one binding mode accessible to ligands within beta-D-galactosidase pocket. The successful pharmacophores were complemented with strict shape constraints in an attempt to optimize their receiver-operating characteristic curve profiles. The validity of the QSAR equations and the associated pharmacophoric models were experimentally established by the identification of several beta-D-galactosidase inhibitors retrieved via in silico search of two structural databases: the National Cancer Institute list of compounds and our in house built structural database of established drugs and agrochemicals. (c) 2010 Wiley Periodicals, Inc. J Comput Chem, 2010.

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Density functional theory investigation of Cu(I)- and Cu(II)-curcumin complexes.

Publication Date: 2010 Aug 20 PMID: 20730779
Authors: Addicoat, M. A. - Metha, G. F. - Kee, T. W.
Journal: J Comput Chem

Density functional theory is used to obtain the lowest energy geometries of bis-aqua curcumin complexes and bis-curcumin complexes of Cu(I) and Cu(II). Three conformations of curcumin, obtained by rotation of the substituted aromatic groups, were considered in each case. Steric repulsion, due to the methoxy-methoxy interactions, was found to be an important factor in determining the lowest energy conformer of Cu(II)(curcumin)(2) but was less important for the Cu(I) analog. Using a sufficiently large basis set, the results show that the lowest energy Cu(II)(curcumin)(2) geometry is square planar around the copper atom, in contrast to the results from a previous study (Shen et al. THEOCHEM-J Mol Struct 2005, 757, 199). In addition, other studies suggested that the formation of this complex is followed by the reduction of Cu(II) to Cu(I). We also examined the singly occupied molecular orbital, spin density, and natural bond orbitals of Cu(II)(curcumin)(2). While the former two analyses show little evidence of electron transfer from curcumin into the Cu center, the latter indicates that Cu(II) is partially reduced to Cu(I) as a consequence of complexation. Finally, we consider the bis-aqua curcumin and bis-curcumin complexes on a reaction path involving progressive displacement of water molecules by curcumin ligands. The results show that the bis-curcumin complex is the most stable Cu(II) complex, showing consistently exothermic steps in the reaction path. However, for Cu(I), the final step in the reaction path is essentially thermoneutral, indicating that the 1:1 and 1:2 Cu(I) complexes are equally stable thermodynamically. (c) 2010 Wiley Periodicals, Inc. J Comput Chem, 2010.

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The quest for the best nonpolarizable water model from the adaptive force matching method.

Publication Date: 2010 Aug 20 PMID: 20730778
Authors: Akin-Ojo, O. - Wang, F.
Journal: J Comput Chem

The recently introduced adaptive force matching (AFM) method is used to develop a significantly improved pair-wise nonpolarizable potential for water. A rigid version of the potential is also presented to enable larger time steps for biological simulations. In this work, it is demonstrated that the AFM method can be used to systematically assess the importance of each functional term during the construction of a force field. For a water potential, it is established that a single off-atom charge center (M) in the plane of water outperforms two out-of-plane charge sites for reproducing intermolecular forces. The four-site pair-wise nonpolarizable force field developed in this work rivals some of the most sophisticated polarizable models in terms of reproducing accurate ab initio forces. The force fields are parameterized to perform best in the temperature range from 0 to 40 degrees C. Equilibrium and dynamical properties calculated with the flexible and rigid force fields are in good agreement with experimental results. For the flexible model, the agreement improves when path integral simulation is performed. These force fields provide high-quality results at a very low computational cost and are thus well suited to atomistic scale biological simulations. The AFM method provides a mechanism for selecting important terms in force field expressions and is a very promising tool for producing accurate force fields in condensed phases. (c) 2010 Wiley Periodicals, Inc. J Comput Chem, 2010.

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Effect of ligand binding on the intraminimum dynamics of proteins.

Publication Date: 2010 Aug 20 PMID: 20730777
Authors: Alakent, B. - Baskan, S. - Doruker, P.
Journal: J Comput Chem

Effects of ligand binding on protein dynamics are studied via molecular dynamics (MD) simulations on two different enzymes, dihydrofolate reductase (DHFR) and triosephosphate isomerase (TIM), in their unliganded (free) and liganded states. Domain motions in MD trajectories are analyzed by collectivities and rotation angles along the principal components (PCs). DHFR in the free state has well-defined domain rotations, whereas rotations are slightly damped in the binary complex with nicotinamide adenine dinucleotide phosphate (NADPH), and remarkably distorted in the presence of NADP(+), showing that NADP(+) is solely responsible for the loss of correlation of the domains in DHFR. Although mean square fluctuations of MD simulations in the same PC subspaces are similar for different ligation states, linear stochastic time series models show that backbone flexibility along the first five PCs is decreased upon NADPH and NADP(+) binding in subpicosecond scale. This shows that mobility of the protein along the PCs is closely related with intraminimum dynamics, and alterations in ligation states may change the intraminimum dynamics significantly. Low vibrational frequencies of the alpha-carbon atoms of DHFR are determined from the time series models of a larger number of low indexed PCs, and it is found that number of modes in the lowest frequencies is reduced upon ligand binding. A similar result is obtained for TIM in the unliganded and dihydroxyacetone phosphate bound states. We suggest that stochastic time series modeling is a promising method to be used in determining subtle perturbations in protein dynamics. (c) 2010 Wiley Periodicals, Inc. J Comput Chem, 2010.

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Nucleic acid sequence design via efficient ensemble defect optimization.

Publication Date: 2010 Aug 17 PMID: 20717905
Authors: Zadeh, J. N. - Wolfe, B. R. - Pierce, N. A.
Journal: J Comput Chem

We describe an algorithm for designing the sequence of one or more interacting nucleic acid strands intended to adopt a target secondary structure at equilibrium. Sequence design is formulated as an optimization problem with the goal of reducing the ensemble defect below a user-specified stop condition. For a candidate sequence and a given target secondary structure, the ensemble defect is the average number of incorrectly paired nucleotides at equilibrium evaluated over the ensemble of unpseudoknotted secondary structures. To reduce the computational cost of accepting or rejecting mutations to a random initial sequence, candidate mutations are evaluated on the leaf nodes of a tree-decomposition of the target structure. During leaf optimization, defect-weighted mutation sampling is used to select each candidate mutation position with probability proportional to its contribution to the ensemble defect of the leaf. As subsequences are merged moving up the tree, emergent structural defects resulting from crosstalk between sibling sequences are eliminated via reoptimization within the defective subtree starting from new random subsequences. Using a Theta(N(3)) dynamic program to evaluate the ensemble defect of a target structure with N nucleotides, this hierarchical approach implies an asymptotic optimality bound on design time: for sufficiently large N, the cost of sequence design is bounded below by 4/3 the cost of a single evaluation of the ensemble defect for the full sequence. Hence, the design algorithm has time complexity Omega(N(3)). For target structures containing N in{100,200,400,800,1600,3200} nucleotides and duplex stems ranging from 1 to 30 base pairs, RNA sequence designs at 37 degrees C typically succeed in satisfying a stop condition with ensemble defect less than N/100. Empirically, the sequence design algorithm exhibits asymptotic optimality and the exponent in the time complexity bound is sharp. (c) 2010 Wiley Periodicals, Inc. J Comput Chem, 2010.

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Second-order state-specific multireference Moller Plesset perturbation theory: Application to energy surfaces of diimide, ethylene, butadiene, and cyclobutadiene.

Publication Date: 2010 Aug 3 PMID: 20683857
Authors: Mahapatra, U. S. - Chattopadhyay, S. - Chaudhuri, R. K.
Journal: J Comput Chem

The complete active space spin-free state-specific multireference Moller-Plesset perturbation theory (SS-MRMPPT) based on the Rayleigh-Schrodinger expansion has proved to be very successful in describing electronic states of model and real molecular systems with predictive accuracy. The SS-MRMPPT method (which deals with one state while using a multiconfigurational reference wave function) is designed to avoid intruder effects along with a balanced description of both dynamic and static correlations in a size-extensive manner, which allows us to produce accurate potential energy surfaces (PESs) with a correct shape in bond-breaking processes. The SS-MRMPPT method is size consistent when localized orbitals on each fragment are used. The intruder state(s) almost inevitably interfere when computing the PESs involving the breaking of genuine chemical bonds. In such situations, the traditional effective Hamiltonian formalism often goes down, so that no physically acceptable solution can be obtained. In this work, we continue our analysis of the SS-MRMPPT method for systems and phenomena that cannot be described either with the conventional single-reference approach or effective Hamiltonian-based traditional MR methods. In this article, we investigate whether the encouraging results we have obtained at the SS-MRMPPT level in the study of cis-trans isomerization of diimide (N(2)H(2)), ethylene (C(2)H(4)), and 1,3-butadiene (C(4)H(6)) carry over to the study of chemical reactions. The energy surfaces of the double-bond flipping interconversion of the two equivalent ground and two lowest singlet state structures of cyclobutadiene have also been studied. All results have been discussed and assessed by comparing with other state-of-the-art calculations and corresponding experimental data whenever available. (c) 2010 Wiley Periodicals, Inc. J Comput Chem, 2010.

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A comment to the nudged elastic band method.

Publication Date: 2010 Oct PMID: 20652994
Authors: Quapp, W. - Bofill, J. M.
Journal: J Comput Chem

The minimum energy path (MEP) is an important reaction path concept of theoretical chemistry, and the nudged elastic band (NEB) method with its many facets is a central method to determine the MEP. We demonstrate in this comment that the NEB does not have to lead to a steepest descent pathway (as always assumed). In contrast, as long as it is used without spring forces, it can lead to a gradient extremal.

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Implementation of an algorithm based on the Runge-Kutta-Fehlberg technique and the potential energy as a reaction coordinate to locate intrinsic reaction paths.

Publication Date: 2010 Oct PMID: 20652993
Authors: Aguilar-Mogas, A. - Gimenez, X. - Bofill, J. M.
Journal: J Comput Chem

The intrinsic reaction coordinate (IRC) curve is used widely as a representation of the Reaction Path and can be parameterized taking the potential energy as a reaction coordinate (Aguilar-Mogas et al., J Chem Phys 2008, 128, 104102). Taking this parameterization and its variational nature, an algorithm is proposed that permits to locate this type of curve joining two points from an arbitrary curve that joints the same initial and final points. The initial and final points are minima of the potential energy surface associated with the geometry of reactants and products of the reaction whose mechanism is under study. The arbitrary curves are moved toward the IRC curve by a Runge-Kutta-Fehlberg technique. This technique integrates a set of differential equations resulting from the minimization until value zero of the line integral over the Weierstrass E-function. The Weierstrass E-function is related with the second variation in the theory of calculus of variations. The algorithm has been proved in real chemical systems.

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Improvements of network approach for analysis of the folding free-energy surface of peptides and proteins.

Publication Date: 2010 Oct PMID: 20652992
Authors: Jiang, X. - Chen, C. - Xiao, Y.
Journal: J Comput Chem

Folding network is an effective approach to investigate the high-dimensional free-energy surface of peptide and protein folding, and it can avoid the limitations of the projected free-energy surface based on two-order parameters. In this article, we present improvements of the effectiveness and accuracy of the folding network analysis based on Markov cluster (MCL) algorithm. We used this approach to investigate the folding free-energy surface of the beta-hairpin peptide trpzip2 and found the folding network is able to determine the basins and folding paths of trpzip2 more clearly and accurately than the two-dimensional free-energy surface.

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Density functional theory study of the oxidation of methanol to formaldehyde on a hydrated vanadia cluster.

Publication Date: 2010 Oct PMID: 20652991
Authors: Gonzalez-Navarrete, P. - Gracia, L. - Calatayud, M. - Andres, J.
Journal: J Comput Chem

Density functional theory was used to study the mechanism for the oxidation of methanol to formaldehyde. A vanadium oxide cluster O=V(OH)(3) has been utilized to represent the catalytic system under hydrated conditions, i.e., in the presence of V-OH hydroxyl groups. Two types of methoxy-intermediates have been considered: a penta-coordinate methoxy-intermediate (OH)(4)V(OCH(3)) and a tetrahedral methoxy-intermediate (OH)(2)VO(OCH(3))(H(2)O). The most plausible reaction pathway corresponds to the process involving first the formation of the tetrahedral methoxide, and a subsequent rate-limiting step where hydrogen is transferred from the methoxy groups toward the oxygen atom of the vanadyl V=O site. The reaction mechanism is a typical two-state reactivity process due to a change of the multiplicity (reactive singlet --> product triplet) along the reaction coordinate accompanied by a reduction of the vanadium center from V(V) (d(0)) to V(III) (d(2)). Minimum energy crossing points were localized and possible spin inversion processes are discussed by means of the intrinsic reaction coordinate approach to find the most favorable reaction pathways. The hydration effect is found to be mainly the destabilization of the methoxy intermediates. An alternative reaction pathway with a lower apparent barrier is presented.

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Theoretical studies on the formation mechanism and explosive performance of nitro-substituted 1,3,5-triazines.

Publication Date: 2010 Oct PMID: 20652990
Authors: Yang, K. - Park, Y. H. - Cho, S. G. - Lee, H. W. - Kim, C. K. - Koo, H. J.
Journal: J Comput Chem

To develop new highly energetic materials, we have considered the design of molecules with high nitrogen content. Possible candidates include 1,3,5-triazine derivatives. In this work, we studied potential synthetic routes for melamine using the MP2/6-31+G(d,p)//B3LYP/6-31G(d) level of theory. The mechanisms studied here are stepwise mechanism beginning with the dimerization of cyanamide and one-step termolecular mechanism. The same type of mechanism is also applied to nitro-substituted 1,3,5-triazines. Values for the heat of formation in the solid phase were predicted from density functional theory calculations. Densities were estimated from a regression equation obtained by molecular surface electrostatic potentials. The Cheetah program was used to study the explosive performance of these compounds. In this study, we found that the explosive properties of 2-amino-4, 6-dinitro-1, 3,5-triazine (ADNTA), and 2,4,6-trinitro-1,3,5-triazine (TNTA) are similar to those of RDX and HMX, respectively.

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Adsorption of CO on oxygen preadsorbed neutral and charged gas phase Pd(4) clusters: A density functional study.

Publication Date: 2010 Oct PMID: 20652989
Authors: Kalita, B. - Deka, R. C.
Journal: J Comput Chem

We present the results of a density functional calculation on adsorption of O(2), CO, and their coadsorption at various sites of neutral, cationic, and anionic Pd(4) clusters. For all the clusters, the dissociative adsorption of oxygen sitting on Pd bridge sites is found to be preferable. Both O(2) and CO binding energies are found to be higher for the anionic Pd(4) cluster followed by cationic and neutral cluster. However, binding energies of O(2) or CO in the coadsorption complexes follow the trend: anionic > neutral > cationic.

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Communications on quantum similarity (2): A geometric discussion on holographic electron density theorem and confined quantum similarity measures.

Publication Date: 2010 Oct PMID: 20652988
Authors: Carbo-Dorca, R. - Besalu, E.
Journal: J Comput Chem

The so-called holographic electron density theorem (HEDT) is analyzed from an algebraic perspective, and a brief analytical point of view is also given. The connection of the HEDT with quantum similarity measures (QSM) over electronic density functions (DF) is studied using GTO functions, atomic ASA DF, and promolecular ASA DF. Restricted integration of QSM over a box of finite side length is discussed for all this DF. This work emphasizes the geometric aspects of HEDT, but for the sake of completeness, some analytical insight based on a general Taylor series expansion is also given at the end.

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Force field parameters for the simulation of modified histone tails.

Publication Date: 2010 Oct PMID: 20652987
Authors: Grauffel, C. - Stote, R. H. - Dejaegere, A.
Journal: J Comput Chem

We describe the development of force field parameters for methylated lysines and arginines, and acetylated lysine for the CHARMM all-atom force field. We also describe a CHARMM united-atom force field for modified sidechains suitable for use with fragment-based docking methods. The development of these parameters is based on results of ab initio quantum mechanics calculations of model compounds with subsequent refinement and validation by molecular mechanics and molecular dynamics simulations. The united-atom parameters are tested by fragment docking to target proteins using the MCSS procedure. The all-atom force field is validated by molecular dynamics simulations of multiple experimental structures. In both sets of calculations, the computational predictions using the force field were compared to the corresponding experimental structures. We show that the parameters yield an accurate reproduction of experimental structures. Together with the existing CHARMM force field, these parameters will enable the general modeling of post-translational modifications of histone tails.

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Solving the low dimensional Smoluchowski equation with a singular value basis set.

Publication Date: 2010 Oct PMID: 20652986
Authors: Scott, G. - Gruebele, M.
Journal: J Comput Chem

Reaction kinetics on free energy surfaces with small activation barriers can be computed directly with the Smoluchowski equation. The procedure is computationally expensive even in a few dimensions. We present a propagation method that considerably reduces computational time for a particular class of problems: when the free energy surface suddenly switches by a small amount, and the probability distribution relaxes to a new equilibrium value. This case describes relaxation experiments. To achieve efficient solution, we expand the density matrix in a basis set obtained by singular value decomposition of equilibrium density matrices. Grid size during propagation is reduced from (100-1000)(N) to (2-4)(N) in N dimensions. Although the scaling with N is not improved, the smaller basis set nonetheless yields a significant speed up for low-dimensional calculations. To demonstrate the practicality of our method, we couple Smoluchowsi dynamics with a genetic algorithm to search for free energy surfaces compatible with the multiprobe thermodynamics and temperature jump experiment reported for the protein alpha(3)D.

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Using one-step perturbation to predict the effect of changing force-field parameters on the simulated folding equilibrium of a beta-peptide in solution.

Publication Date: 2010 Oct PMID: 20652985
Authors: Lin, Z. - Liu, H. - van Gunsteren, W. F.
Journal: J Comput Chem

Computer simulation using molecular dynamics is increasingly used to simulate the folding equilibria of peptides and small proteins. Yet, the quality of the obtained results depends largely on the quality of the force field used. This comprises the solute as well as the solvent model and their energetic and entropic compatibility. It is, however, computational very expensive to perform test simulations for each combination of force-field parameters. Here, we use the one-step perturbation technique to predict the change of the free enthalpy of folding of a beta-peptide in methanol solution due to changing a variety of force-field parameters. The results show that changing the solute backbone partial charges affects the folding equilibrium, whereas this is relatively insensitive to changes in the force constants of the torsional energy terms of the force field. Extending the cut-off distance for nonbonded interactions beyond 1.4 nm does not affect the folding equilibrium. The same result is found for a change of the reaction-field permittivity for methanol from 17.7 to 30. The results are not sensitive to the criterion, e.g., atom-positional RMSD or number of hydrogen bonds, that is used to distinguish folded and unfolded conformations. Control simulations with perturbed Hamiltonians followed by backward one-step perturbation indicated that quite large perturbations still yield reliable results. Yet, perturbing all solvent molecules showed where the limitations of the one-step perturbation technique are met. The evaluated methodology constitutes an efficient tool in force-field development for molecular simulation by reducing the number of required separate simulations by orders of magnitude.

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Molecular tailoring approach in conjunction with MP2 and Ri-MP2 codes: A comparison with fragment molecular orbital method.

Publication Date: 2010 Oct PMID: 20652984
Authors: Rahalkar, A. P. - Katouda, M. - Gadre, S. R. - Nagase, S.
Journal: J Comput Chem

Many Divide-and-Conquer based approaches are being developed to overcome the high scaling problem of the ab initio methods. In this work, one such method, Molecular Tailoring Approach (MTA) has been interfaced with recently developed efficient Moller-Plesset second order perturbation theory (MP2) codes viz. IMS-MP2 and RI-MP2 to reap the advantage of both. An external driver script is developed for implementing MTA at the front-end and the MP2 codes at the back-end. The present version of the driver script is written only for a single point energy evaluation of a molecular system at a fixed geometry. The performance of these newly developed MTA-IMS-MP2 and MTA-RI-MP2 codes is extensively benchmarked for a variety of molecular systems vis-a-vis the corresponding actual runs. In addition to this, the performance of these programs is also critically compared with Fragment Molecular Orbital (FMO), another popular fragment-based method. It is observed that FMO2/2 is superior to FMO3/2 and MTA with respect to time advantage; however, the errors of FMO2 are much beyond chemical accuracy. However, FMO3/2 is a highly accurate method for biological systems but is unsuccessful in case of water clusters. MTA produces estimates with errors within 1 kcal/mol uniformly for all systems with reasonable time advantage. Analysis carried out employing various basis sets shows that FMO gives its optimum performance only for basis sets, which does not include diffuse functions. On the contrary, MTA performance is found to be similar for any basis set used.

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Symmetry measures of the electron density.

Publication Date: 2010 Oct PMID: 20652983
Authors: Casanova, D. - Alemany, P. - Alvarez, S.
Journal: J Comput Chem

In this communication we define electronic symmetry operation and symmetry group measures, eSOM and eSGM, respectively, develop the basic algorithms to obtain them, and give some examples of the possible applications of these new computational tools. These new symmetry measures based on the electron density have been tested in an analysis of (a) the inversion symmetry for heteronuclear diatomic molecules, for the eclipsed and staggered conformations of ethane and tetrafluoroethane, and for a series of octahedral sulfur halides; (b) the reflection symmetry of three different conformers of tetrafluoroethene; and (c) the loss of C(6) symmetry along the B(2u) distortion mode of benzene and an analysis of rotational symmetry for different six-member ring heterocycles.

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Parallel Fock matrix construction with distributed shared memory model for the FMO-MO method.

Publication Date: 2010 Oct PMID: 20652982
Authors: Umeda, H. - Inadomi, Y. - Watanabe, T. - Yagi, T. - Ishimoto, T. - Ikegami, T. - Tadano, H. - Sakurai, T. - Nagashima, U.
Journal: J Comput Chem

A parallel Fock matrix construction program for FMO-MO method has been developed with the distributed shared memory model. To construct a large-sized Fock matrix during FMO-MO calculations, a distributed parallel algorithm was designed to make full use of local memory to reduce communication, and was implemented on the Global Array toolkit. A benchmark calculation for a small system indicates that the parallelization efficiency of the matrix construction portion is as high as 93% at 1,024 processors. A large FMO-MO application on the epidermal growth factor receptor (EGFR) protein (17,246 atoms and 96,234 basis functions) was also carried out at the HF/6-31G level of theory, with the frontier orbitals being extracted by a Sakurai-Sugiura eigensolver. It takes 11.3 h for the FMO calculation, 49.1 h for the Fock matrix construction, and 10 min to extract 94 eigen-components on a PC cluster system using 256 processors.

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Application of ant colony optimization in development of models for prediction of anti-HIV-1 activity of HEPT derivatives.

Publication Date: 2010 Sep PMID: 20575016
Authors: Zare-Shahabadi, V. - Abbasitabar, F.
Journal: J Comput Chem

Quantitative structure-activity relationship models were derived for 107 analogs of 1-[(2-hydroxyethoxy) methyl]-6-(phenylthio)thymine, a potent inhibitor of the HIV-1 reverse transcriptase. The activities of these compounds were investigated by means of multiple linear regression (MLR) technique. An ant colony optimization algorithm, called Memorized_ACS, was applied for selecting relevant descriptors and detecting outliers. This algorithm uses an external memory based upon knowledge incorporation from previous iterations. At first, the memory is empty, and then it is filled by running several ACS algorithms. In this respect, after each ACS run, the elite ant is stored in the memory and the process is continued to fill the memory. Here, pheromone updating is performed by all elite ants collected in the memory; this results in improvements in both exploration and exploitation behaviors of the ACS algorithm. The memory is then made empty and is filled again by performing several ACS algorithms using updated pheromone trails. This process is repeated for several iterations. At the end, the memory contains several top solutions for the problem. Number of appearance of each descriptor in the external memory is a good criterion for its importance. Finally, prediction is performed by the elitist ant, and interpretation is carried out by considering the importance of each descriptor. The best MLR model has a training error of 0.47 log (1/EC(50)) units (R(2) = 0.90) and a prediction error of 0.76 log (1/EC(50)) units (R(2) = 0.88).

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Polarizable empirical force field for sulfur-containing compounds based on the classical Drude oscillator model.

Publication Date: 2010 Sep PMID: 20575015
Authors: Zhu, X. - MacKerell, A. D. Jr
Journal: J Comput Chem

Condensed-phase computational studies of molecules using molecular mechanics approaches require the use of force fields to describe the energetics of the systems as a function of structure. The advantage of polarizable force fields over nonpolarizable (or additive) models lies in their ability to vary their electronic distribution as a function of the environment. Toward development of a polarizable force field for biological molecules, parameters for a series of sulfur-containing molecules are presented. Parameter optimization was performed to reproduce quantum mechanical and experimental data for gas phase properties including geometries, conformational energies, vibrational spectra, and dipole moments as well as for condensed phase properties such as heats of vaporization, molecular volumes, and free energies of hydration. Compounds in the training set include methanethiol, ethanethiol, propanethiol, ethyl methyl sulfide, and dimethyl disulfide. The molecular volumes and heats of vaporization are in good accordance with experimental values, with the polarizable model performing better than the CHARMM22 nonpolarizable force field. Improvements with the polarizable model were also obtained for molecular dipole moments and in the treatment of intermolecular interactions as a function of orientation, in part due to the presence of lone pairs and anisotropic atomic polarizability on the sulfur atoms. Significant advantage of the polarizable model was reflected in calculation of the dielectric constants, a property that CHARMM22 systematically underestimates. The ability of this polarizable model to accurately describe a range of gas and condensed phase properties paves the way for more accurate simulation studies of sulfur-containing molecules including cysteine and methionine residues in proteins.

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Branch migration of Holliday junction in RuvA tetramer complex studied by umbrella sampling simulation using a path-search algorithm.

Publication Date: 2010 Sep PMID: 20575014
Authors: Ishida, H.
Journal: J Comput Chem

Branch migration of the Holliday junction takes place at the center of the RuvA tetramer. To elucidate how branch migration occurs, umbrella sampling simulations were performed for complexes of the RuvA tetramer and Holliday junction DNA. Although conventional umbrella sampling simulations set sampling points a priori, the umbrella sampling simulation in this study set the sampling points one by one in order to search for a realistic path of the branch migration during the simulations. Starting from the X-ray structure of the complex, in which the hydrogen bonds between two base-pairs were unformed, the hydrogen bonds between the next base-pairs of the shrinking stems were observed to start to disconnect. At the intermediate stage, three or four of the eight unpaired bases interacted closely with the acidic pins from RuvA. During the final stage, these bases moved away from the pins and formed the hydrogen bonds of the new base-pairs of the growing stems. The free-energy profile along this reaction path showed that the intermediate stage was a meta-stable state between two free-energy barriers of about 10 to 15 kcal/mol. These results imply that the pins play an important role in stabilizing the interactions between the pins and the unpaired base-pairs.

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Multidimensionality of delocalization indices and nucleus-independent chemical shifts in polycyclic aromatic hydrocarbons II: proof of further nonlocality.

Publication Date: 2010 Sep PMID: 20575013
Authors: Fias, S. - Van Damme, S. - Bultinck, P.
Journal: J Comput Chem

In a recent contribution, we examined the effect of 10- and 14-center circuits on the nucleus-independent chemical shifts NICSs using multicenter bond indices (MCBIs) (Fias et al., J Comput Chem 2008, 29, 358). In this study, the nonlocal contributions to the NICS are further investigated for a larger set of polycyclic aromatic hydrocarbons (PAHs). To achieve this, the NICSs are predicted using the MCBI and compared with ab initio results. The NICSs of the central ring of perylene- and benzo-[ghi]perylene-like fragments and of coronene appear to have other nonlocal contributions than the ones previously studied. It is shown that a model based on the MCBI-ring current maps and the inclusion of new circuits proves the existence and shows the nature of these new nonlocal effects on the NICS. This new model leads to a better understanding of the differences between the NICSs and delocalization indices. The results show that the NICS value is not only significantly influenced by the higher order circuits encircling the ring at which it is evaluated but also by the local aromaticity of the surrounding rings, and occasionally, like in the case of coronene, the NICSs are even influenced by currents farther away in the molecule.

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Theoretical investigation of an energetic fullerene derivative.

Publication Date: 2010 Sep PMID: 20575012
Authors: Tan, B. - Peng, R. - Li, H. - Jin, B. - Chu, S. - Long, X.
Journal: J Comput Chem

A self-consistent estimation method for the thermochemical properties of N-methyl-3-(2',4',6'-trinitrobenzene)-fulleropyrrolidine (MTNBFP) is presented. This method is based on enthalpy of formation (Delta(f)H(m)(minus sign in circle)) and enthalpy of combustion obtained from BLYP/DNP calculations of the total energies and frequencies for MTNBFP. The enthalpy of formation was calculated by an optimized set of isodesmic reactions given the available experimental Delta(f)H(m)(minus sign in circle) of relative compounds. MTNBFP has a high enthalpy of formation, 2782.2 kJ/mol. Detonation velocity and detonation pressure were also presented in terms of Kamlet and Jacobs equations. Drop hammer impact sensitivity tests and blasting point per 5 s tests indicate MTNBFP may be a potential candidate primary explosive. To understand the test results well, we proposed a series of chemical reaction mechanisms and interpreted the relationship between impact sensitivity and electronic structures from the viewpoint of nitro group charge, electrostatic potential, and vibrational modes.

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A theoretical study on the catalytic mechanism of Mus musculus adenosine deaminase.

Publication Date: 2010 Sep PMID: 20575011
Authors: Wu, X. H. - Zou, G. L. - Quan, J. M. - Wu, Y. D.
Journal: J Comput Chem

The catalytic mechanism of Mus musculus adenosine deaminase (ADA) has been studied by quantum mechanics and two-layered ONIOM calculations. Our calculations show that the previously proposed mechanism, involving His238 as the general base to activate the Zn-bound water, has a high activation barrier of about 28 kcal/mol at the proposed rate-determining nucleophilic addition step, and the corresponding calculated kinetic isotope effects are significantly different from the recent experimental observations. We propose a revised mechanism based on calculations, in which Glu217 serves as the general base to abstract the proton of the Zn-bound water, and the protonated Glu217 then activates the substrate for the subsequent nucleophilic addition. The rate-determining step is the proton transfer from Zn-OH to 6-NH(2) of the tetrahedral intermediate, in which His238 serves as a proton shuttle for the proton transfer. The calculated kinetic isotope effects agree well with the experimental data, and calculated activation energy is also consistent with the experimental reaction rate.

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Computational studies on the mechanism and kinetics of Cl reaction with C2H5I.

Publication Date: 2010 Sep PMID: 20575010
Authors: Jia, X. J. - Liu, Y. J. - Sun, J. Y. - Sun, H. - Wang, F. - Su, Z. M. - Pan, X. M. - Wang, R. S.
Journal: J Comput Chem

The dual-level direct kinetics method has been used to investigate the multichannel reactions of C(2)H(5)I + Cl. Three hydrogen abstraction channels and one displacement process are found for the title reaction. The calculation indicates that the hydrogen abstraction from -CH(2)- group is the dominant reaction channel, and the displacement process may be negligible because of the high barrier. The rate constants for individual reaction channels are calculated by the improved canonical variational transition-state theory with small-curvature tunneling correction over the temperature range of 220-1500 K. Our results show that the tunneling correction plays an important role in the rate constant calculation in the low-temperature range. Agreement between the calculated and experimental data available is good. The Arrhenius expression k(T) = 2.33 x 10(-16) T(1.83) exp(-185.01/T) over a wide temperature range is obtained. Furthermore, the kinetic isotope effects for the reaction C(2)H(5)I + Cl are estimated so as to provide theoretical estimation for future laboratory investigation.

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Theoretical study of the microhydration of mononuclear and dinuclear uranium(VI) species derived from solvolysis of uranyl nitrate in water.

Publication Date: 2010 Sep PMID: 20340110
Authors: Oncak, M. - Schroder, D. - Slavicek, P.
Journal: J Comput Chem

The structures and energetics of mononuclear and dinuclear uranium species formed upon speciation of uranyl(VI) nitrate, UO(2)(NO(3))(2), in water are investigated by quantum chemistry using density functional theory and the wavefunction-based methods (MP2, CCSD, CCSD(T)). We provide a discussion of the basic coordination patterns of the various mono- and dinuclear uranyl compounds [(UO(2))(m)(X,Y)(2m-1)(H2O)(n)](+) (m = 1, 2; n = 0-4) found in a recent mass spectrometric study (Tsierkezos et al., Inorg Chem 2009, 48, 6287). The energetics of the complexation of the uranyl dication to the counterions OH(-) and NO(3) (-) as well as the degradation of the dinuclear species were studied by reference to a test set of 16 representative molecules with the MP2 method and the B3LYP, M06, M06-HF, and M06-2X DFT functionals. All DFT functionals provide structures and energetics close to MP2 results, with M06 family being slightly superior to the standard B3LYP functional.

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ForceFit: a code to fit classical force fields to quantum mechanical potential energy surfaces.

Publication Date: 2010 Sep PMID: 20340109
Authors: Waldher, B. - Kuta, J. - Chen, S. - Henson, N. - Clark, A. E.
Journal: J Comput Chem

The ForceFit program package has been developed for fitting classical force field parameters based upon a force matching algorithm to quantum mechanical gradients of configurations that span the potential energy surface of the system. The program, which runs under UNIX and is written in C++, is an easy-to-use, nonproprietary platform that enables gradient fitting of a wide variety of functional force field forms to quantum mechanical information obtained from an array of common electronic structure codes. All aspects of the fitting process are run from a graphical user interface, from the parsing of quantum mechanical data, assembling of a potential energy surface database, setting the force field, and variables to be optimized, choosing a molecular mechanics code for comparison to the reference data, and finally, the initiation of a least squares minimization algorithm. Furthermore, the code is based on a modular templated code design that enables the facile addition of new functionality to the program.

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Electron localizability indicators ELI-D and ELIA for highly correlated wavefunctions of homonuclear dimers. II. N2, O2, F2, and Ne2.

Publication Date: 2010 Sep PMID: 20340107
Authors: Bezugly, V. - Wielgus, P. - Kohout, M. - Wagner, F. R.
Journal: J Comput Chem

Electron localizability indicators based on the electron pair density ELI-D and ELIA Electron localizability indicators ELI-D and ELIA based on the electron pair density are studied for the correlated ground-state wavefunctions of N(2), O(2), F(2), and Ne(2) diatomics. Different basis sets and reference spaces are used for the multireference configuration interaction method following the complete active space calculations to investigate the local effect of electron correlation on the extent of electron localizability in position space determined by the two indicators. The results are complemented by calculations of effective bond order, vibrational frequency, and Laplacian of the electron density at the bond midpoint. It turns out that for O(2) and F(2), the reliable topology of ELI-D is obtained only at the correlated level of theory.

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Modeling of diarylalkyl-imidazole and diarylalkyl-triazole derivatives as potent aromatase inhibitors for treatment of hormone-dependent cancer.

Publication Date: 2010 Sep PMID: 20340106
Authors: Nagar, S. - Saha, A.
Journal: J Comput Chem

Aromatase is an enzyme that catalyzes the final step in the conversion of androgen to estrogen. It has become an attractive target for the treatment of estrogen responsive breast cancer. The study has been focused on designing aromatase inhibitors (AIs) that can be selected as probable drug candidate for the treatment of breast cancer. In the present study, long chain diarylalkyl-imidazole and -triazole scaffolds have been considered for exploring pharmacophores as potent AIs using QSAR (Quantitative SAR) and pharmacophore mapping studies. The model generated in linear free energy QSAR study (R(2) = 0.905, Q(2)= 0.885, R(2)(pred(ts)) = 0.763) showed the importance of hydrophobicity, size and shape of the molecule, van der Waals surface and hydrogen atom contribution influence the activity. 3D QSAR of comparative molecular field analysis (CoMFA, R(2)= 0.921, Q(2) = 0.741, R(2)(pred(ts))= 0.583) showed that steric and electrostatic features along with hydrophobicity and electronic charge contribution at C(4) (Fig. 1) influence on the inhibitory activity. Comparative molecular similarity analysis (CoMSIA, R(2) = 0.874, Q(2) = 0.716, R(2)(pred(ts)) = 0.591) study adjudged the presence of steric, electrostatic and hydrophobic fields together with hydrogen bond (HB) donor and acceptor play significant role in inhibitory activity to aromatase enzyme. Further pharmacophore mapping study (Q(2) = 0.947, Delta(cost) = 113.171, R(2)(pred(ts)) = 0.857) suggested that presence of HB acceptor, hydrophobicity with aromatic ring, and the importance of steric contribution influence on the activity. The critical distances among the features are also important for the inhibitor activity.

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Molecular docking studies of selected tricyclic and quinone derivatives on trypanothione reductase of Leishmania infantum.

Publication Date: 2010 Oct PMID: 20340105
Authors: Venkatesan, S. K. - Shukla, A. K. - Dubey, V. K.
Journal: J Comput Chem

Visceral leishmaniasis, most lethal form of Leishmaniasis, is caused by Leishmania infantum in the Old world. Current therapeutics for the disease is associated with a risk of high toxicity and development of drug resistant strains. Thiol-redox metabolism involving trypanothione and trypanothione reductase, key for survival of Leishmania, is a validated target for rational drug design. Recently published structure of trypanothione reductase (TryR) from L. infantum, in oxidized and reduced form along with Sb(III), provides vital clues on active site of the enzyme. In continuation with our attempts to identify potent inhibitors of TryR, we have modeled binding modes of selected tricyclic compounds and quinone derivatives, using AutoDock4. Here, we report a unique binding mode for quinone derivatives and 9-aminoacridine derivatives, at the FAD binding domain. A conserved hydrogen bonding pattern was observed in all these compounds with residues Thr335, Lys60, His461. With the fact that these residues aid in the orientation of FAD towards the active site forming the core of the FAD binding domain, designing selective and potent compounds that could replace FAD in vivo during the synthesis of Trypanothione reductase can be deployed as an effective strategy in designing new drugs towards Leishmaniasis. We also report the binding of Phenothiazine and 9-aminoacridine derivatives at the Z site of the protein. The biological significance and possible mode of inhibition by quinone derivatives, which binds to FAD binding domain, along with other compounds are discussed.

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A toolkit to assist ONIOM calculations.

Publication Date: 2010 Sep PMID: 20340103
Authors: Tao, P. - Schlegel, H. B.
Journal: J Comput Chem

A general procedure for quantum mechanics and molecular mechanics (QM/MM) studies on biochemical systems is outlined, and a collection of PERL scripts to facilitate ONIOM-type QM/MM calculations is described. This toolkit is designed to assist in the different stages of an ONIOM QM/MM study of biomolecules, including input file preparation and checking, job monitoring, production calculations, and results analysis. An iterative procedure for refitting the partial charges of QM region atoms is described and yields a more accurate treatment of the electrostatic interaction between QM and MM regions during QM/MM calculations. The toolkit fully supports this partial charge-refitting procedure. By using this toolkit for file conversions, structure manipulation, input sanity checks, parameter lookup, charge refitting, tracking optimizations, and analyzing results, QM/MM studies of large size biochemical systems can be much more convenient and practical.

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Theoretical studies on the structure and protonation of Cu(II) complexes of a series of tripodal aliphatic tetraamines: Good correlations with the experimental data.

Publication Date: 2010 Oct PMID: 20340102
Authors: Salehzadeh, S. - Bayat, M.
Journal: J Comput Chem

DFT(B3LYP) studies on first protonation step of a series of Cu(II) complexes of some tripodal tetraamines with general formula N[(CH(2))(n)NH(2)][(CH(2))(m)NH(2)][(CH(2))(p)NH(2)] (n = m = p = 2, tren; n = 3, m = p = 2, pee; n = m = 3, p = 2, ppe; n = m = 3, tpt; n = 2, m = 3, p = 4, epb; and n = m = 3, p = 4; ppb) are reported. First, the gas-phase proton macroaffinity of all latter complexes was calculated with considering following simple reaction: [Cu(L)](2+)(g) + H(+)(g) --> [Cu(HL)](3+)(g). The results showed that there is a good correlation between the calculated proton macroaffinities of all complexes with their stability constants in solution. Then, we tried to determine the possible reliable structures for microspecies involved in protonation process of above complexes. The results showed that, similar to the solid state, the [Cu(L)(H(2)O)](2+) and [Cu(HL)(H(2)O)(2)](3+) are most stable species for latter complexes and their protonated form, respectively, at gas phase. We found that there are acceptable correlations between the formation constants of above complexes with both the -Delta E and -Delta G of following reaction: [Cu(L)(H(2)O)](2+)(g) + H(+)(g) + H(2)O(g) --> [Cu(HL)(H(2)O)(2)](3+)(g). The -Delta E of the latter reaction can be defined as a theoretically solvent-proton macroaffinity of reactant complexes because they have gained one proton and one molecule of the solvent. The unknown formation constant of [Cu(epb)](2+) complex was also predicted from the observed correlations. In addition, the first proton affinity of all complexes was studied in solution using DPCM and CPCM methods. It was shown that there is an acceptable correlation between the solvent-proton affinities of [Cu(L)(H(2)O)](2+) complexes with formation constants of [Cu(HL)(H(2)O)(2)](3+) complexes in solution.

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A computational study on the capability of borane-cyclic boryl anion adducts to act as hydrogen atom donors.

Publication Date: 2010 Sep PMID: 20336800
Authors: Lai, C. H. - Chou, P. T.
Journal: J Comput Chem

According to our theoretical approaches, a cyclic boryl anion can act as a Lewis base like its isoelectronic counterpart N-heterocyclic carbene, reducing the homolytic bond dissociation energy of B-H in BH(3). However, the donating efficiency is affected by the counter cation in both gas phase and nonpolar solvents. Moreover, we also predict the seven-membered ring boryl anion 5, although it has not yet synthesized, to be the most efficient reagent to reduce the bond dissociation energy of a B-H bond in BH(3). This study may thus pave another avenue toward Lewis base induced hydrogen atom abstraction in BH(3).

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Mechanisms of norbornadiene dimerization to Binor-S using cationic Co(I), Rh(I), and Ir(I) catalysts.

Publication Date: 2010 Sep PMID: 20186862
Authors: Wu, Y. - Jin, L. - Xue, Y. - Lee, I. M. - Kim, C. K.
Journal: J Comput Chem

We investigated the transition metal-catalyzed reaction mechanisms of NBD dimerization to Binor-S using cationic Co(I), Rh(I), and Ir(I) catalysts, using mPW1PW91, mPW1K, and B3LYP density functional methods. Our results indicate that the monomeric metal center has the ability to bind with four double bonds of two NBD molecules with a syn spatial geometry to form a penta-coordinated complex. We designed three possible pathways, but found two of them blocked. The favored pathway involves three steps from the reactant precursor to the product precursor: the first step is the formation of a single bond to connect two NBD units, the second is the alkene insertion leading to the formation of the three-membered ring structure, and the final step is the formation of the final product precursor. Orbital analysis showed metal...C-C sigma agostic interaction in the product precursor, which is in agreement with the previous experimental findings. In addition, we found that the solvent and counter-ions had significant effects on the dimerization reactions.

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