scispace - formally typeset
Search or ask a question

Showing papers in "Journal of Computational Chemistry in 1997"


Journal ArticleDOI
TL;DR: Although the derivation of the algorithm is presented in terms of matrices, no matrix matrix multiplications are needed and only the nonzero matrix elements have to be stored, making the method useful for very large molecules.
Abstract: In this article, we present a new LINear Constraint Solver (LINCS) for molecular simulations with bond constraints. The algorithm is inherently stable, as the constraints themselves are reset instead of derivatives of the constraints, thereby eliminating drift. Although the derivation of the algorithm is presented in terms of matrices, no matrix matrix multiplications are needed and only the nonzero matrix elements have to be stored, making the method useful for very large molecules. At the same accuracy, the LINCS algorithm is three to four times faster than the SHAKE algorithm. Parallelization of the algorithm is straightforward. (C) 1997 John Wiley & Sons, Inc.

12,699 citations


Journal ArticleDOI
TL;DR: In this paper, the authors proposed a method to take into account the effect of temperature deviations on kinetic evaluations by combining the isoconversional principle of evaluating the activation energy with numerical integration of the equation.
Abstract: The thermal effect of a reaction makes the temperature inside the reaction system deviate from a prescribed heating program. To take into account the effect of such temperature deviations on kinetic evaluations, a computational method applicable to an arbitrary variation in temperature has been developed. The method combines the isoconversional principle of evaluating the activation energy with numerical integration of the equation, dα/dt = k[T(t)]f(α), over the actual variation of the temperature with the time, T(t). Details of the numerical algorithm are reported. A model example has been used to verify the reliability of this method as compared to an analogous method which does not account for the deviations of the temperature from a prescribed program. The method has been tested for tolerance for noise in the temperature. © 1997 by John Wiley & Sons, Inc.

666 citations


Journal ArticleDOI
TL;DR: In this paper, the OPLS all-atom force field for organic and biomolecular systems has been expanded to include carbohydrates, and geometry optimizations were carried out for 144 conformers at the restricted Hartree-Fock (RHF)/6-31G* level.
Abstract: The OPLS all-atom (AA) force field for organic and biomolecular systems has been expanded to include carbohydrates. Starting with reported nonbonded parameters of alcohols, ethers, and diols, torsional parameters were fit to reproduce results from ab initio calculations on the hexopyranoses, α,β-d-glucopyranose, α,β-d-mannopyranose, α,β-d-galactopyranose, methyl α,β-d-glucopyranoside, and methyl α,β-d-mannopyranoside. In all, geometry optimizations were carried out for 144 conformers at the restricted Hartree–Fock (RHF)/6–31G* level. For the conformers with a relative energy within 3 kcal/mol of the global minima, the effects of electron correlation and basis-set extension were considered by performing single-point calculations with density functional theory at the B3LYP/6–311+G** level. The torsional parameters for the OPLS-AA force field were parameterized to reproduce the energies and structures of these 44 conformers. The resultant force field reproduces the ab initio calculated energies with an average unsigned error of 0.41 kcal/mol. The α/β ratios as well as the relative energies between the isomeric hexopyranoses are in good accord with the ab initio results. The predictive abilities of the force field were also tested against RHF/6–31G* results for d-allopyranose with excellent success; a surprising discovery is that the lowest energy conformer of d-allopyranose is a β anomer. © 1997 John Wiley & Sons, Inc. J Comput Chem18: 1955–1970, 1997

625 citations


Journal ArticleDOI
TL;DR: It is shown that the site point–directed search is tenfold faster than a random search, but that the single graph matching algorithm boosts the speed of database screening up to 60‐fold.
Abstract: The DOCK program explores possible orientations of a molecule within a macromolecular active site by superimposing atoms onto precomputed site points. Here we compare a number of different search methods, including an exhaustive matching algorithm based on a single docking graph. We evaluate the performance of each method by screening a small database of molecules to a variety of macromolecular targets. By varying the amount of sampling, we can monitor the time convergence of scores and rankings. We not only show that the site point–directed search is tenfold faster than a random search, but that the single graph matching algorithm boosts the speed of database screening up to 60‐fold. The new algorithm, in fact, outperforms the bipartite graph matching algorithm currently used in DOCK. The results indicate that a critical issue for rapid database screening is the extent to which a search method biases run time toward the highest‐ranking molecules. The single docking graph matching algorithm will be incorporated into DOCK version 4.0. © 1997 John Wiley & Sons, Inc. J Comput Chem 18: 1175–1189

496 citations


Journal ArticleDOI
TL;DR: In this article, the potentials of both radial and anisotropic type were derived from protein-crystal data and the relative weights of the energy terms were optimized to locate the native structures of selected test proteins as the lowest energy structures.
Abstract: A two-stage procedure for the determination of a united-residue potential designed for protein simulations is outlined. In the first stage, the long-range and local-interaction energy terms of the total energy of a polypeptide chain are determined by analyzing protein-crystal data and averaging the all-atom energy surfaces. In the second stage (described in the accompanying article), the relative weights of the energy terms are optimized so as to locate the native structures of selected test proteins as the lowest energy structures. The goal of the work in the present study is to parameterize physically reasonable functional forms of the potentials of mean force for side-chain interactions. The potentials are of both radial and anisotropic type. Radial potentials include the Lennard-Jones and the shifted Lennard-Jones potential (with the shift parameter independent of orientation). To treat the angular dependence of side-chain interactions, three functional forms of the potential that were designed previously to describe anisotropic systems are evaluated: Berne-Pechukas (dilated Lennard-Jones); Gay-Berne (shifted Lennard-Jones with orientation-dependent shift parameters); and Gay-Berne-Vorobjev (the same as the preceding one, but with one more set of variable parameters). These functional forms were used to parameterize, within a short-distance range, the potentials of mean force for side-chain pair interactions that are related by the Boltzmann principle to the pair correlation functions determined from protein-crystal data. Parameter determination was formulated as a generalized nonlinear least-squares problem with the target function being the weighted sum of squares of the differences between calculated and “experimental” (i.e., estimated from protein-crystal data) angular, radial-angular, and radial pair correlation functions, as well as contact free energies. A set of 195 high-resolution nonhomologous structures from the Protein Data Bank was used to calculate the “experimental” values. The contact free energies were scaled by the slope of the correlation line between side-chain hydrophobicities, calculated from the contact free energies, and those determined by Fauchere and Pliska from the partition coefficients of amino acids between water and n-octanol. The methylene group served to define the reference contact free energy corresponding to that between the glycine methylene groups of backbone residues. Statistical analysis of the goodness of fit revealed that the Gay-Berne-Vorobjev anisotropic potential fits best to the experimental radial and angular correlation functions and contact free energies and therefore represents the free-energy surface of side-chain-side-chain interactions most accurately. Thus, its choice for simulations of protein structure is probably the most appropriate. However, the use of simpler functional forms is recommended, if the speed of computations is an issue. © 1997 by John Wiley & Sons, Inc. J Comput Chem 18: 849–873, 1997

321 citations


Journal ArticleDOI
TL;DR: In this paper, a new adaptive umbrella sampling technique for molecular dynamics simulations is described, which is achieved by using the weighted histogram analysis method to combine the results from different simulations, by a suitable extrapolation scheme to define the umbrella potential for regions that have not been sampled, and by a criterion to identify simulations during which the system was not in equilibrium.
Abstract: A new adaptive umbrella sampling technique for molecular dynamics simulations is described. The high efficiency of the technique renders multidimensional adaptive umbrella sampling possible and thereby enables uniform sampling of the conformational space spanned by several degrees of freedom. The efficiency is achieved by using the weighted histogram analysis method to combine the results from different simulations, by a suitable extrapolation scheme to define the umbrella potential for regions that have not been sampled, and by a criterion to identify simulations during which the system was not in equilibrium. The technique is applied to two test systems, the alanine dipeptide and the threonine dipeptide, to sample the configurational space spanned by one or two dihedral angles. The umbrella potentials applied at the end of each adaptive umbrella sampling run are equal to the negative of the corresponding potentials of mean force. The trajectories obtained in the simulations can be used to calculate dynamical variables that are of interest. An example is the distribution of the distance between the HN and the H b proton that can be important for the interpretation of NMR experiments. Factors influencing the accuracy of the calculated quantities are discussed. Q 1997 John Wiley & Sons, Inc. J Comput Chem 18: 1450)1462, 1997

313 citations


Journal ArticleDOI
TL;DR: In this article, a new optimization method is presented to search for the global minimum energy conformations of polypeptides, which combines essential aspects of the build-up procedure and the genetic algorithm, and introduces the important concept of conformational space annealing.
Abstract: A new optimization method is presented to search for the global minimum-energy conformations of polypeptides. The method combines essential aspects of the build-up procedure and the genetic algorithm, and it introduces the important concept of ''conformational space annealing.'' Instead of considering a single conformation, attention is focused on a population of conformations while new conformations are obtained by modifying a ''seed conformation.'' The annealing is carried out by introducing a distance cutoff, D , which is defined in the conformational space; D effectively divides the cut cut whole conformational space of local minima into subdivisions. The value of D cut is set to a large number at the beginning of the algorithm to cover the whole conformational space, and annealing is achieved by slowly reducing it. Many distinct local minima designed to be distributed as far apart as possible in conformational space are investigated simultaneously. Therefore, the new method finds not only the global minimum-energy conformation but also many other distinct local minima as by-products. The method is tested on Met- enkephalin, a 24-dihedral angle problem. For all 100 independent runs, the accepted global minimum-energy conformation was obtained after about 2600 minimizations on average. Q 1997 by John Wiley & Sons, Inc. J Comput Chem 18: 1222)1232, 1997

282 citations


Journal ArticleDOI
TL;DR: In this paper, the authors compared AMBER 4.1, AM1, MNDO/M, PM3, and the non-empirical ab initio self-consistent field (SCF) method utilizing a minimal basis set combined with the London dispersion energy (SCFD method) for calculation of stabilization energies of 26 H-bonded DNA base pairs.
Abstract: Empirical energy functions (AMBER 4.1, CFF95, CHARMM23, OPLS, Poltev), semiempirical quantum chemical methods (AM1, MNDO/M, PM3), and the nonempirical ab initio self-consistent field (SCF) method utilizing a minimal basis set combined with the London dispersion energy (SCFD method) were used for calculation of stabilization energies of 26 H-bonded DNA base pairs, 10 stacked DNA base pairs (thymine was replaced by uracil), and the B-DNA decamer (only DNA bases were considered). These energies were compared with nonempirical ab initio beyond Hartree–Fock values [second-order Moller–Plesset (MP2)/6–31G*(0.25)]. The best performance was exhibited by AMBER 4.1 with the force field of Cornell et al. The SCFD method, tested for H-bonded pairs only, exhibited stabilization energies that were too large. Semiempirical quantum chemical methods gave poor agreement with MP2 values in the H-bonded systems and failed completely for stacked pairs. A similar failure was recently reported for density functional theory calculations on base stacking. It may be concluded that currently available force fields provide much better descriptions of interactions of nucleic acid bases than the semiempirical methods and low-level ab initio treatment. © 1997 John Wiley & Sons, Inc. J Comput Chem18: 1136–1150

261 citations


Journal ArticleDOI
TL;DR: In this article, a direct transfer of Cartesian molecular force fields FF and electric property tensors is compared to transfer in internal coordinates with an aim to improve simulation of vibrational spectra for larger molecules.
Abstract: A direct transfer of Cartesian molecular force fields FF and electric property tensors is tested on model systems and compared to transfer in internal coordinates with an aim to improve simulation of vibrational spectra for larger molecules. This Cartesian transformation can be implemented easily and offers greater flexibility in practical computations. It can be also applied for transfer of anharmonic derivatives. The results for model calculations of the force field and vibrational frequencies for N-methylacetamide show that our method removes errors associated with numerical artifacts caused by nonlinearity of the otherwise required Cartesian to internal coordinate transformation. For determination of IR absorption and vibrational circular dichroism intensities, atomic polar and axial tensors were also transferred in the Cartesian representation. For the latter, which are dependent upon the magnetic dipole operator, a distributed origin gauge is used to avoid an origin dependence. Comparison of the results of transferring ab initio FF and intensity parameters from an amide dimer fragment onto a tripeptide with those from a conventionally determined tripeptide FF document some limitations of the transfer method and its possible applications in the vibrational spectroscopy. Finally, application to determination of the FF and spectra for helical heptapeptide are presented and compared to experimental results. Q 1997 by John Wiley & Sons, Inc.

211 citations


Journal ArticleDOI
TL;DR: The Hartree-Fock method is combined with both a force field and an ion pair shell model potential in this article, which is designed for use in structure optimizations and is also applicable to molecular dynamics simulations.
Abstract: A computational scheme is presented which combines quantum mechanical ab initio techniques with methods using analytical potential functions. The scheme is designed for use in structure optimizations and is also applicable to molecular dynamics simulations. The implementation covers both molecular and periodic systems. The problem of the link atoms is solved by a subtraction scheme which is easily implemented for any combination of methods. As a first application dense and microporous silica polymorphs are studied. The Hartree-Fock method is combined with both a force field and an ion pair shell model potential. Comparison is made with lattice energy minimizations which use the force field or the shell model potential alone as well as with free cluster optimizations and optimizations in which the outer part of the cluster is kept fixed. © 1997 by John Wiley & Sons, Inc.

175 citations


Journal ArticleDOI
TL;DR: In this paper, the authors determined and parameterized appropriate functional forms for the local interaction terms, corresponding to the rotation about the virtual bonds (Utor), the bending of virtual-bond angles (Ub), and the energy of different rotameric states of side chains (Urot).
Abstract: Continuing our work on the determination of an off‐lattice united‐residue force field for protein‐structure simulations, we determined and parameterized appropriate functional forms for the local‐interaction terms, corresponding to the rotation about the virtual bonds (Utor), the bending of virtual‐bond angles (Ub), and the energy of different rotameric states of side chains (Urot). These terms were determined by applying the Boltzmann principle to the distributions of virtual‐bond torsional and virtual‐bond angles and side‐chain rotameric states, respectively, calculated from a data base of 195 high‐resolution nonhomologous proteins. The complete energy function was constructed by combining the individual energy terms with appropriate weights. The weights were determined by optimizing the so‐called Z‐score value (which is the normalized difference between the energy of the native structure and the mean energy of non‐native structures) of the histidine‐containing phosphocarrier protein from Streptococcus faecalis (1PTF; an 88‐residue α + β protein). To accomplish this, a database of Cα patterns was created using high‐resolution nonhomologous protein structures from the Protein Data Bank, and the distributions of energy components of 1PTF were obtained by threading its sequence through ∼500 randomly chosen Cα‐patterns from the X‐ray structures in the PDB, followed by energy minimization, with the energy function incorporating initially guessed weights. The resulting minimized energies were used to optimize the Z‐score value of 1PTF as a function of the weights of the various energy terms, and the new weights were used to generate new energy‐component distributions. The process was iterated, until the weights used to generate the distributions and the optimized weights were self‐consistent. The potential function with the weights of the various energy terms obtained by optimizing the Z‐score value for 1PTF was found to locate the native structures of other test proteins (within an average RMS deviation of 3 Å): calcium‐binding protein (4ICB), ubiquitin (1UBQ), α‐spectrin (1SHG), major cold‐shock protein (1MJC), and cytochrome b5 (3B5C) (which included α and β structures) as distinctively lowest in energy in similar threading experiments. © 1997 by John Wiley & Sons, Inc. J Comput Chem 18: 874–887, 1997

Journal ArticleDOI
TL;DR: In this paper, a distributed multipole analysis (DMA)-based description of the electrostatic energy, and intermolecular perturbation theory (IMPT) calculations, hydrogen bonding between donor alkanol hydroxyl groups and oxygen acceptor atoms in ketone, ether, and ester functional groups is characterized.
Abstract: An attractive way to study intermolecular hydrogen bonding is to combine analysis of experimental crystallographic data with ab initio—based energy calculations. Using the Cambridge Structural Database (CSD), a distributed multipole analysis (DMA)-based description of the electrostatic energy, and intermolecular perturbation theory (IMPT) calculations, hydrogen bonding between donor alkanol hydroxyl groups and oxygen acceptor atoms in ketone, ether, and ester functional groups is characterized. The presence and absence of lone pair directionality to carbonyl and ether or ester oxygens, respectively, can be explained in terms of favored electrostatic energies, the major attractive contribution in hydrogen bonding. A hydrogen bond in its optimum geometry is only slightly stronger when formed to a ketone group than to an ether group. Hydrogen bonds formed to carbonyl groups have similar properties in a ketone or ester, but the ester O2 differs from an ether oxygen due to various environmental effects rather than a change in its intrinsic properties. For (E)-ester oxygens, there are few hydrogen bonds found in the CSD because of the competition with the adjacent carbonyl group, but the interaction energies are similar to an ether. Hydrogen bonds to O2 of (Z)-esters are destabilized by the repulsive electrostatic interaction with the carbonyl group. The relative abundance of nonlinear hydrogen bonds found in the CSD can be explained by geometrical factors, and is also due to environmental effects producing slightly stronger intermolecular interaction energies for an off-linear geometry. © 1997 by John Wiley & Sons, Inc. J Comput Chem 18: 757–774, 1997

Journal ArticleDOI
TL;DR: ORAC as mentioned in this paper is a molecular dynamics program for simulation of complex molecular systems that combines state-of-the-art molecular dynamics MD algorithms with flexibility in handling different types and sizes of molecules.
Abstract: In this study, we present a new molecular dynamics program for simulation of complex molecular systems. The program, named ORAC, combines . state-of-the-art molecular dynamics MD algorithms with flexibility in handling different types and sizes of molecules. ORAC is intended for simulations of molecular systems and is specifically designed to treat biomolecules efficiently and effectively in solution or in a crystalline environment. Among its unique . features are: i implementation of reversible and symplectic multiple time step . algorithms or r-RESPA, reversible reference system propagation algorithm specifically designed and tuned for biological systems with periodic boundary . conditions; ii availability for simulations with multiple or single time steps of . standard Ewald or smooth particle mesh Ewald SPME for computation of . electrostatic interactions; and iii possibility of simulating molecular systems in a variety of thermodynamic ensembles. We believe that the combination of these algorithms makes ORAC more advanced than other MD programs using standard simulation algorithms. Q 1997 John Wiley & Sons, Inc. J Comput Chem 18: 1848)1862, 1997

Journal ArticleDOI
TL;DR: In this paper, the CHARMM22 all-hydrogen parameters for proteins, nucleic acids, and lipids were developed for use in modeling of the coenzymes nicotinamide adenine dinucleotide (NAD+) and NAD hydride.
Abstract: Empirical force field parameters for nicotinamide (NIC+) and 1,4-dihydronicotinamide (NICH) were developed for use in modeling of the coenzymes nicotinamide adenine dinucleotide (NAD+) and NAD hydride (NADH). The parametrization follows the methodology used in the development of the CHARMM22 all-hydrogen parameters for proteins, nucleic acids, and lipids. Parametrization of inorganic phosphate for use in adenosine di- and triphosphates (e.g., ADP and ATP) is also presented. While high level ab initio data, such as conformational energies, dipole moments, interactions with water, and vibrational frequencies, were adequately reproduced by the developed parameters, strong emphasis was placed on the successful reproduction of experimental geometries and crystal data. Results for molecular dynamics crystal simulations were in good agreement with available crystallographic data. Simulations of NAD+ in the enzyme alcohol dehydrogenase compared quite favorably with experimental geometries and protein matrix interactions. © 1997 by John Wiley & Sons, Inc.

Journal ArticleDOI
TL;DR: In this paper, an automatic three-dimensional mesh generation system for molecular geometries developed in our laboratory is used to solve the Poisson-Boltzmann equation numerically using a finite element method.
Abstract: The automatic three-dimensional mesh generation system for molecular geometries developed in our laboratory is used to solve the Poisson–Boltzmann equation numerically using a finite element method. For a number of different systems, the results are found to be in good agreement with those obtained in finite difference calculations using the DelPhi program as well as with those from boundary element calculations using our triangulated molecular surface. The overall scaling of the method is found to be approximately linear in the number of atoms in the system. The finite element mesh structure can be exploited to compute the gradient of the polarization energy in 10–20% of the time required to solve the equation itself. The resulting timings for the larger systems considered indicate that energies and gradients can be obtained in about half the time required for a finite difference solution to the equation. The development of a multilevel version of the algorithm as well as future applications to structure optimization using molecular mechanics force fields are also discussed. © 1997 John Wiley & Sons, Inc. J Comput Chem18: 1591–1608, 1997

Journal ArticleDOI
TL;DR: In this paper, a method for diagonalizing large covariance matrices is presented, and the stability of the essential space during a simulation is investigated by comparing the two halves of a trajectory.
Abstract: Recently the basic theory of essential dynamics, a method for extracting large concerted motions from protein molecular dynamics trajectories, was described. Here, we introduce and test new aspects. A method for diagonalizing large covariance matrices is presented. We show that it is possible to perform essential dynamics using different subsets of atoms and compare these to the basic C-or analysis. Essential dynamics analyses are also compared to the normal modes method. The stability of the essential space during a simulation is investigated by comparing the two halves of a trajectory. Apart from the analyses in Cartesian space, the essential dynamics in phi/psi torsion angle space is discussed. (C) 1997 by John Wiley & Sons, Inc.

Journal ArticleDOI
TL;DR: N numerically compare the effectiveness of three recently proposed algorithms, multicanonical algorithm, simulations in a 1/k‐sampling, and simulated tempering, for the protein folding problem, finding that the differences among the three are only marginal.
Abstract: We numerically compare the effectiveness of three recently proposed algorithms, multicanonical algorithm, simulations in a 1/k-sampling, and simulated tempering, for the protein folding problem. We perform simulations with high statistics for one of the simplest peptides, met-enkephalin. While the performances of all three approaches is much better than traditional methods, we find that the differences among the three are only marginal. © 1997 by John Wiley & Sons, Inc. J Comput Chem 18: 920–933, 1997

Journal ArticleDOI
TL;DR: GARANT as discussed by the authors is a program for automatic resonance assignment of nuclear magnetic resonance (NMR) spectra of proteins, which is based on a scoring scheme able to distinguish between correct and incorrect resonance assignments.
Abstract: A new program for automatic resonance assignment of nuclear magnetic resonance (NMR) spectra of proteins, GARANT (General Algorithm for Resonance AssignmeNT), is introduced. Three principal elements used in this approach are: (a) representation of resonance assignments as an optimal match of two graphs describing, respectively, peaks expected from combined knowledge of the primary structure and the magnetization transfer pathways in the spectra used, and experimentally observed peaks; (b) a scoring scheme able to distinguish between correct and incorrect resonance assignments; and (c) combination of an evolutionary algorithm with a local optimization routine. The score that evaluates the match of expected peaks to observed peaks relies on the agreement of the information available about these peaks, most prominently, but not exclusively, the chemical shifts. Tests show that the combination of an evolutionary algorithm and a local optimization routine yields results that are clearly superior to those obtained when using either of the two techniques separately in the search for the correct assignments. GARANT is laid out for assignment problems involving peaks observed in two- and three-dimensional homonuclear and heteronuclear NMR spectra of proteins. © 1997 by John Wiley & Sons, Inc.

Journal ArticleDOI
TL;DR: In this paper, the rational function (RF) and direct inversion in the iterative subspace (DIIS) methods are compared and optimized for the purpose of geometry optimization, and the most effective and stable procedure for optimization of equilibrium structures was found to be the DIIS minimization in natural internal coordinates using the BFGS update of the model Hessian.
Abstract: Various geometry optimization techniques are systematically investigated. The rational function (RF) and direct inversion in the iterative subspace (DIIS) methods are compared and optimized for the purpose of geometry optimization. Various step restriction and line search procedures are tested. The model Hessian recently proposed by Lindh et al. has been used in conjunction with different Hessian update procedures. Optimization for over 30 molecules have been performed in Z‐matrix coordinates, local normal coordinates, and curvilinear natural internal coordinates, using the same approximations for the Hessian in all cases. The most effective and stable procedure for optimization of equilibrium structures was found to be the DIIS minimization in natural internal coordinates using the BFGS update of the model Hessian. Our method shows faster overall convergence than all previously published methods for the same test suite of molecules. © 1997 John Wiley & Sons, Inc. J Comput Chem 18: 1473–1483, 1997

Journal ArticleDOI
TL;DR: A new docking program that explores ligand flexibility is developed that can be applied to database searches and most of the top‐ranking molecules are dihydrofolate or methotrexate derivatives, which are known to be DHFR inhibitors, demonstrating the suitability of this program for screening molecular databases.
Abstract: We have developed a new docking program that explores ligand flexibility. This program can be applied to database searches. The program is similar in concept to earlier efforts, but it has been automated and improved. The algorithm begins by selecting an anchor fragment of a ligand. This fragment is protonated, as needed, and then placed in the receptor by the DOCK algorithm, followed by minimization using a simplex method. Finally, the conformations of the remaining parts of the putative ligands are searched by a limited backtrack method and minimized to get the most stable conformation. To test the efficiency of this method, the program was used to regenerate ten ligand–protein complex structures. In all cases, the docked ligands basically reproduced the crystallographic binding modes. The efficiency of this method was further tested by a database search. Ten percent of molecules from the Available Chemicals Directory (ACD) were docked to a dihydrofolate reductase structure. Most of the top-ranking molecules (7 of the top 13 hits) are dihydrofolate or methotrexate derivatives, which are known to be DHFR inhibitors, demonstrating the suitability of this program for screening molecular databases. © 1997 John Wiley & Sons, Inc. J Comput Chem18: 1812–1825, 1997

Journal ArticleDOI
TL;DR: In this article, it was shown that HOMO-LUMO energy differences obtained with the B3LYP, B3P86, and B 3PW91 functionals are in good agreement with vertical excitation energies from UV-absorption spectra.
Abstract: Band gaps in solids and excitation energies in finite systems are underestimated significantly if estimated from differences between eigenvalues obtained within the local spin density approximation (LSDA). In this article we present results on 20 small- and medium-sized π-systems which show that HOMO–LUMO energy differences obtained with the B3LYP, B3P86, and B3PW91 functionals are in good agreement with vertical excitation energies from UV-absorption spectra. The improvement is a result of the use of the exact Hartree–Fock exchange with hybrid methods. Negative HOMO energies and negative LUMO energies do not provide good estimates for IPs and EAs. In contrast to Hartree–Fock theory, where IPs are approximated well and EAs are given poorly, DFT hybrid methods underestimate IPs and EAs by about the same amount. LSDA yields reasonable EAs but poor IPs. © 1997 John Wiley & Sons, Inc. J Comput Chem18: 1943–1953, 1997

Journal ArticleDOI
TL;DR: In this paper, the performance of four commonly used density functionals (VWN, BLYP, BP91, and Becke's original three-parameter approximation to the adiabatic connection formula, referred to herein as the ACM) was studied with a series of six Gaussian-type atomic basis sets.
Abstract: The performance of four commonly used density functionals (VWN, BLYP, BP91, and Becke's original three-parameter approximation to the adiabatic connection formula, referred to herein as the adiabatic connection method or ACM) was studied with a series of six Gaussian-type atomic basis sets [DZP, 6–31G**, DZVP, TZVP, TZ2P, and uncontracted aug-cc-pVTZ (UCC)]. The geometries and dipole moments of over 100 first-row and second-row molecules and reaction energies of over 300 chemical reactions involving such molecules were computed using each of the four density functionals in combination with each of the six basis sets. The results were compared to experimentally determined values. Based on overall mean absolute theory versus experiment errors, it was found that ACM is the best choice for predictions of both energies of reaction [overall mean absolute theory versus experiment error (MATvEE) of 4.7 kcal/mol with our most complete (UCC) basis set] and molecular geometries (overall MATvEE of 0.92 pm for bond distances and 0.88° for bond angles with the UCC basis set). For routine calculations with moderate basis sets (those of double-ζ type: DZP, 6–31G**, and DZVP) the DZVP basis set was, on average, the best choice. There were, however, examples of reactions where significantly larger basis sets were required to achieve reasonable accuracy (errors ≤ 5 kcal/mol). For dipole moments, ACM, BP91, and BLYP performed comparably (overall MATvEE of 0.071, 0.067, and 0.059 debye, respectively, with the UCC basis set). Basis sets that include additional polarization functions and diffuse functions were found to be important for accurate density functional theory predictions of dipole moments. © 1997 by John Wiley & Sons, Inc.

Journal ArticleDOI
TL;DR: In this paper, the performance of B•LYP, B•P86, B3-P86 and B3•PW91 density functionals to describe multiple hydrogen bond systems was studied.
Abstract: The performance of B‐LYP, B‐P86, B3‐LYP, B3‐P86, and B3‐PW91 density functionals to describe multiple hydrogen bond systems was studied. For this purpose we have chosen the dimers of hydrogen peroxide and the hydrogen peroxide–water complexes. The geometries and vibrational frequencies obtained with a 6‐311+G(d,p) basis set were compared with those obtained at the MP2 level using the same basis set expansion. The corresponding dimerization energies were obtained using a 6‐311+G(3df,2p) basis set and compared with those obtained using the G2(MP2) theory. Red shiftings of the OH donor stretching frequencies were predicted by all approaches investigated; however, in all cases, the DFT values were sizably larger than the MP2 ones. Similarly, the blue shifting of the torsion of the hydrogen peroxide subunit was larger when evaluated at the DFT level. All functionals reproduced the G2(MP2) relative stabilities of the different local minima quite well. With the exception of the B‐LYP and B3‐PW91 approaches, all functionals yielded binding energies which deviated from the G2(MP2) values by less than 0.5 kcal/mol, provided that G2‐type basis sets were used and that the corresponding BSSE corrections were included. © 1997 John Wiley & Sons, Inc. J Comput Chem 18: 1124–1135

Journal ArticleDOI
TL;DR: In this paper, a fast multigrid boundary element (MBE) method for solving the Poisson equation for macromolecular electrostatic calculations in a solvent is developed, which uses an adaptive tesselation of the molecular surface by BEs with nonregular size.
Abstract: A fast multigrid boundary element (MBE) method for solving the Poisson equation for macromolecular electrostatic calculations in a solvent is developed. To convert the integral equation of the BE method into a numerical linear equation of low dimensions, the MBE method uses an adaptive tesselation of the molecular surface by BEs with nonregular size. The size of the BEs increases in three successive levels as the uniformity of the electrostatic field on the molecular surface increases. The MBE method provides a high degree of consistency, good accuracy, and stability when the sizes of the BEs are varied. The computational complexity of the unrestricted MBE method scales as O(Nat), where Nat is the number of atoms in the macromolecule. The MBE method is ideally suited for parallel computations and for an integrated algorithm for calculations of solvation free energy and free energy of ionization, which are coupled with the conformation of a solute molecule. The current version of the 3-level MBE method is used to calculate the free energy of transfer from a vacuum to an aqueous solution and the free energy of the equilibrium state of ionization of a 17-residue peptide in a given conformation at a given pH in ∼ 400 s of CPU time on one node of the IBM SP2 supercomputer. © 1997 by John Wiley & Sons, Inc. J Comput Chem18: 569–583, 1997

Journal ArticleDOI
TL;DR: A computational approach to the inclusion of off-center charges in both additive and non-additive molecular mechanics calculations is presented in this article, where additional sites in the molecular skeleton are placed in the approximate locations of the chemically intuitive electron lone pair, and are treated as formal particles throughout the calculation.
Abstract: A computational approach to the inclusion of off-center charges in both additive and nonadditive molecular mechanics calculations is presented. The additional sites in the molecular skeleton are placed in the approximate locations of the chemically intuitive electron lone pair, and are treated as formal particles throughout the calculation. The increase in the number of charge sites results in overall improvement in the energy associated with the angular dependence of hydrogen bonds and improved statistical accuracy of the electrostatic potential derived charges. The addition of lone pairs also results in improved accuracy in relative solvation free energy calculation for the pyridine to benzene and methanol to methane mutations. Because the number of atoms that require lone pairs is small, the extra accuracy can be achieved with little computational overhead. © 1997 John Wiley & Sons, Inc. J Comput Chem18: 1632–1646, 1997

Journal ArticleDOI
TL;DR: In this paper, the solvent response is described by means of point charges chosen in such a way that they reproduce the average value of the solvent electrostatic potential calculated from molecular dynamics data.
Abstract: We present the theory and implementation of a new approach for studying solvent effects. The electronic structure of the solute, calculated at the ab initio level, is obtained in the presence of the surrounding medium. We employ a mean field theory in which the solvent response is described by means of point charges chosen in such a way that they reproduce the average value of the solvent electrostatic potential calculated from molecular dynamics data. In this way, the complete solvent potential can be introduced into the solute Hamiltonian without making use of a one-center multiple expansion of the solute-solvent potential. In the proposed method, only one quantum calculation has to be performed and a great number of configurations can easily be included making the calculation statistically significant. We show that, despite the large fluctuations in the solute charge distribution induced by the solvent, the proposed mean field theory adequately reproduces the energetics and properties of formamide and water molecules in aqueous solution. © 1997 by John Wiley & Sons, Inc.

Journal ArticleDOI
TL;DR: It is shown for Verlet‐I/r‐RESPA multiple time stepping, which is based on approximating long‐range forces as widely separated impulses, that a long time step of 5 fs results in a dramatic energy drift and that this is reduced by using an even largerlong time step.
Abstract: Numerical experiments are performed on a 36,000-atom protein)DNA)water simulation to ascertain the effectiveness of two devices for reducing the time spent computing long-range electrostatics interactions. It is shown for Verlet-Irr-RESPA multiple time stepping, which is based on approximating long-range forces as widely separated impulses, that a long time step of 5 fs results in a dramatic energy drift and that this is reduced by using an even larger long time step. It is also shown that the use of as many as six terms in a fast multipole algorithm approximation to long-range electrostatics still fails to prevent significant energy drift even though four digits of accuracy is obtained. Q 1997 John Wiley & Sons, Inc. J Comput Chem 18: 1785)1791, 1997

Journal ArticleDOI
TL;DR: The directionality and relative strengths of hydrogen bonds to monocyclic aromatic heterocycles were investigated using crystal structure data and theoretical calculations Surveys of the Cambridge Structural Database for hydrogen bonds between C(sp3)O(SINGLE BOND)H and aromatic fragments containing one or more nitrogen and/or oxygen heteroatoms as discussed by the authors.
Abstract: The directionality and relative strengths of hydrogen bonds to monocyclic aromatic heterocycles were investigated using crystal structure data and theoretical calculations Surveys of the Cambridge Structural Database for hydrogen bonds between C(sp3)(SINGLE BOND)O(SINGLE BOND)H and aromatic fragments containing one or more nitrogen and/or oxygen heteroatoms showed that hydrogen bonds to nitrogen atoms are much more abundant than to oxygen Distinct preferred orientations were also revealed in these surveys Theoretical calculations were performed on the interaction of methanol with pyridine, pyrimidine, pyrazine, pyridazine, oxazole, isoxazole, 1,2,4-oxadiazole, and furan as models for the heterocyclic fragments The intermolecular potential surface was thoroughly scanned using a model potential that accurately described the electrostatic forces (derived from distributed multipole analysis) with empirical parameters for the repulsion and dispersion terms Minima on this surface agreed well with the observed orientations in the data base and they were typically deeper for nitrogen than for oxygen acceptors, although the hydrogen bond strength and geometry was influenced by other heteroatoms in the ring These results were confirmed by highly accurate intermolecular perturbation theory calculations, which also estimated the deviations from hydrogen bonding in the traditional nitrogen lone pair direction that could occur with negligible reduction in the interaction energy © 1997 John Wiley & Sons, Inc J Comput Chem18: 2060–2074, 1997

Journal ArticleDOI
TL;DR: In this article, the elementary Jacobi rotations technique is used to obtain fitted electronic density functions expressed as linear combinations of atomic spherical shells, with the additional constraint that all coefficients are kept positive.
Abstract: The elementary Jacobi rotations technique is proposed as a useful tool to obtain fitted electronic density functions expressed as linear combinations of atomic spherical shells, with the additional constraint that all coefficients are kept positive. Moreover, a Newton algorithm has been implemented to optimize atomic shell exponents, minimizing the quadratic error integral function between ab initio and fitted electronic density functions. Although the procedure is completely general, as an application example both techniques have been used to compute a 1S-type Gaussian basis for atoms H through Kr, fitted from a 3-21G basis set. Subsequently, molecular electronic densities are modeled in a promolecular approximation, as a simple sum of parameterized atomic contributions. This simple molecular approximation has been employed to show, in practice, its usefulness to some computational examples in the field of molecular quantum similarity measures. © 1997 John Wiley & Sons, Inc. J Comput Chem18: 2023–2039, 1997

Journal ArticleDOI
TL;DR: The electron localization function (ELF) shows too high values when computed from valence densities only (instead of using the total density) as mentioned in this paper, and this effect is mainly found when d electrons are present in the outermost shell of the core.
Abstract: The electron localization function (ELF) shows too-high values when computed from valence densities only (instead of using the total density). This effect is mainly found when d electrons are present in the outermost shell of the core. Although no pronounced qualitative differences could be noticed in the examples studied up to now, it is found that the quantitative differences between the values of ELF obtained from the valence densities only or from the total densities can be large. We also show, for the first time, an example (the Be atom) where ELF is obtained directly from the density. This exemplifies the possibility of computing ELF from highly accurate calculations (or from experimental data). © 1997 John Wiley & Sons, Inc. J Comput Chem18: 1431–1439, 1997