Stewart Computational Chemistry

COLORADO SPRINGS, CO, United States

Stewart Computational Chemistry

COLORADO SPRINGS, CO, United States
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Dutra J.D.L.,Federal University of Sergipe | Filho M.A.M.,Federal University of Sergipe | Rocha G.B.,Federal University of Paraiba | Freire R.O.,Federal University of Sergipe | And 2 more authors.
Journal of Chemical Theory and Computation | Year: 2013

The recently published Parametric Method number 7, PM7, is the first semiempirical method to be successfully tested by modeling crystal structures and heats of formation of solids. PM7 is thus also capable of producing results of useful accuracy for materials science and constitutes a great improvement over its predecessor, PM6. In this article, we present Sparkle model parameters to be used with PM7 that allow the prediction of geometries of metal complexes and materials which contain lanthanide trications. Accordingly, we considered the geometries of 224 high-quality crystallographic structures of complexes for the parametrization set and 395 more for the validation of the parametrization for the whole lanthanide series, from La(III) to Lu(III). The average unsigned error for Sparkle/PM7 for the distances between the metal ion and its coordinating atoms is 0.063 Å for all lanthanides, ranging from a minimum of 0.052 Å for Tb(III) to 0.088 Å for Ce(III), comparable to the equivalent errors in the distances predicted by PM7 for other metals. These distance deviations follow a gamma distribution within a 95% level of confidence, signifying that they appear to be random around a mean, confirming that Sparkle/PM7 is a well-tempered method. We conclude by carrying out a Sparkle/PM7 full geometry optimization of two spatial groups of the same thulium-containing metal organic framework, with unit cells accommodating 376 atoms, of which 16 are Tm(III) cations; the optimized geometries were in good agreement with the crystallographic ones. These results emphasize the capability of the use of the Sparkle model for the prediction of geometries of compounds containing lanthanide trications within the PM7 semiempirical model, as well as the usefulness of such semiempirical calculations for materials modeling. Sparkle/PM7 is available in the software package MOPAC2012, at no cost for academics and can be obtained from http://openmopac.net. © 2013 American Chemical Society.


Rozanska X.,Materials Design S.a.r.l. | Stewart J.J.P.,Stewart Computational Chemistry | Ungerer P.,Materials Design S.a.r.l. | Leblanc B.,Materials Design S.a.r.l. | And 3 more authors.
Journal of Chemical and Engineering Data | Year: 2014

The atomistic and molecular simulation environment MedeA (MedeA: Materials Exploration and Design Analysis, version 2.14.6; Material Design, Inc.: Angel Fire, NM, 1998-2014; http://www.materialsdesign.com) in its functionalities and graphical user interface has been enhanced to prepare and submit on the order of 1000 simulations on different structures, and to collect and help in the analysis of the results. We illustrate this with the determination of the accuracy of the semiempirical (SE) package MOPAC2012 (Stewart, J. J. P. MOPAC2012; Stewart Computational Chemistry: Colorado Springs, CO, USA, 2012; http://OpenMOPAC.net) with the PM7 method (Stewart, J. J. P. Optimization of parameters for semiempirical methods VI: more modifications to the NDDO approximations and reoptimization of parameters. J. Mol. Model. 2013, 19, 1-32) to compute frequencies of vibration and thermodynamic properties, specifically the zero point energies, ideal gas heat capacity at constant pressure, entropy, and Gibbs free energy, between 200 and 1000 K for 795 organic molecules. The results were compared with experimental data and density functional theory (DFT) values (using B3LYP/TZVP and BP86/TZVP DFT methods). This comparison showed that the PM7 frequencies of vibration above 2500 cm-1 are systematically underestimated. An a posteriori correction using a linear relationship rescaling of the frequencies permitted resetting to zero the average relative deviations with respect to experimental reference values. This frequency correction also removed the bias from the zero point energies, ideal gas heat capacity, and entropy average deviations from the PM7 results. The root-mean-square deviation (RMSD) of PM7 and the DFT heat capacities of 160 organic molecules were equivalent with respect to experimental values, being about 5 %, 2.5 %, and 3 % at 300 K, 600 K, and 1000 K, respectively. The RMSD of PM7, when compared to the DFT values, became 4 %, 2 %, and 1 % for the same temperatures when the analysis was extended to a set of 795 molecules. In the case of the ideal gas entropies, the RMSD of the PM7 relative to DFT values were between 5 % and 4 % between 300 K and 1000 K, respectively. The RMSD of the Gibbs free energies of PM7 were 15 kJ mol-1 and 30 kJ mol-1 at 300 K and 1000 K, respectively. The efficiency of this semiempirical approach was tested on a set of approximately 5800 molecules. This set was processed in about a day, thus demonstrating the scalability of the approach to big data sets. © 2014 American Chemical Society.


Harvey M.J.,Imperial College London | Mason N.J.,Imperial College London | McLean A.,Imperial College London | Murray-Rust P.,Center for Molecular Informatics | And 2 more authors.
Journal of Cheminformatics | Year: 2015

Background: The desirable curation of 158,122 molecular geometries derived from the NCI set of reference molecules together with associated properties computed using the MOPAC semi-empirical quantum mechanical method and originally deposited in 2005 into the Cambridge DSpace repository as a data collection is reported. Results: The procedures involved in the curation included annotation of the original data using new MOPAC methods, updating the syntax of the CML documents used to express the data to ensure schema conformance and adding new metadata describing the entries together with a XML schema transformation to map the metadata schema to that used by the DataCite organisation. We have adopted a granularity model in which a DataCite persistent identifier (DOI) is created for each individual molecule to enable data discovery and data metrics at this level using DataCite tools. Conclusions: We recommend that the future research data management (RDM) of the scientific and chemical data components associated with journal articles (the "supporting information") should be conducted in a manner that facilitates automatic periodic curation. © 2015 Harvey et al.


Wick C.R.,The Interdisciplinary Center | Hennemann M.,The Interdisciplinary Center | Stewart J.J.P.,Stewart Computational Chemistry | Clark T.,The Interdisciplinary Center | Clark T.,University of Portsmouth
Journal of Molecular Modeling | Year: 2014

Proteins in the gas phase present an extreme (and unrealistic) challenge for self-consistent-field iteration schemes because their ionized groups are very strong electron donors or acceptors, depending on their formal charge. This means that gas-phase proteins have a very small band gap but that their frontier orbitals are localized compared to "normal" conjugated semiconductors. The frontier orbitals are thus likely to be separated in space so that they are close to, but not quite, orthogonal during the SCF iterations. We report full SCF calculations using the massively parallel EMPIRE code and linear scaling localized-molecular-orbital (LMO) calculations using Mopac2009. The LMO procedure can lead to artificially over-polarized wavefunctions in gas-phase proteins. The full SCF iteration procedure can be very slow to converge because many cycles are needed to overcome the over-polarization by inductive charge shifts. Example molecules have been constructed to demonstrate this behavior. The two approaches give identical results if solvent effects are included. © 2014 Springer-Verlag.


Martin B.P.,University of Colorado at Boulder | Brandon C.J.,University of Colorado at Boulder | Stewart J.J.P.,University of Colorado at Boulder | Stewart J.J.P.,Stewart Computational Chemistry | And 2 more authors.
Proteins: Structure, Function and Bioinformatics | Year: 2015

Using the semiempirical method PM7, an attempt has been made to quantify the error in prediction of the in vivo structure of proteins relative to X-ray structures. Three important contributory factors are the experimental limitations of X-ray structures, the difference between the crystal and solution environments, and the errors due to PM7. The geometries of 19 proteins from the Protein Data Bank that had small R values, that is, high accuracy structures, were optimized and the resulting drop in heat of formation was calculated. Analysis of the changes showed that about 10% of this decrease in heat of formation was caused by faults in PM7, the balance being attributable to the X-ray structure and the difference between the crystal and solution environments. A previously unknown fault in PM7 was revealed during tests to validate the geometries generated using PM7. Clashscores generated by the Molprobity molecular mechanics structure validation program showed that PM7 was predicting unrealistically close contacts between nonbonding atoms in regions where the local geometry is dominated by very weak noncovalent interactions. The origin of this fault was traced to an underestimation of the core-core repulsion between atoms at distances smaller than the equilibrium distance. © 2015 The Authors.


Stewart J.J.P.,Stewart Computational Chemistry
Journal of Molecular Modeling | Year: 2016

A new method for predicting the energy contributions to substrate binding and to specificity has been developed. Conventional global optimization methods do not permit the subtle effects responsible for these properties to be modeled with sufficient precision to allow confidence to be placed in the results, but by making simple alterations to the model, the precisions of the various energies involved can be improved from about ±2 kcal mol−1 to ±0.1 kcal mol−1. This technique was applied to the oxidized nucleotide pyrophosphohydrolase enzyme MTH1. MTH1 is unusual in that the binding and reaction sites are well separated—an advantage from a computational chemistry perspective, as it allows the energetics involved in docking to be modeled without the need to consider any issues relating to reaction mechanisms. In this study, two types of energy terms were investigated: the noncovalent interactions between the binding site and the substrate, and those responsible for discriminating between the oxidized nucleotide 8-oxo-dGTP and the normal dGTP. Both of these were investigated using the semiempirical method PM7 in the program MOPAC. The contributions of the individual residues to both the binding energy and the specificity of MTH1 were calculated by simulating the effect of mutations. Where comparisons were possible, all calculated results were in agreement with experimental observations. This technique provides fresh insight into the binding mechanism that enzymes use for discriminating between possible substrates. © 2016, The Author(s).


Stewart J.J.P.,Stewart Computational Chemistry
Journal of Molecular Modeling | Year: 2013

Modern semiempirical methods are of sufficient accuracy when used in the modeling of molecules of the same type as used as reference data in the parameterization. Outside that subset, however, there is an abundance of evidence that these methods are of very limited utility. In an attempt to expand the range of applicability, a new method called PM7 has been developed. PM7 was parameterized using experimental and high-level ab initio reference data, augmented by a new type of reference data intended to better define the structure of parameter space. The resulting method was tested by modeling crystal structures and heats of formation of solids. Two changes were made to the set of approximations: a modification was made to improve the description of noncovalent interactions, and two minor errors in the NDDO formalism were rectified. Average unsigned errors (AUEs) in geometry and ΔH f for PM7 were reduced relative to PM6; for simple gas-phase organic systems, the AUE in bond lengths decreased by about 5 % and the AUE in ΔH f decreased by about 10 %; for organic solids, the AUE in ΔH f dropped by 60 % and the reduction was 33.3 % for geometries. A two-step process (PM7-TS) for calculating the heights of activation barriers has been developed. Using PM7-TS, the AUE in the barrier heights for simple organic reactions was decreased from values of 12.6 kcal/mol-1 in PM6 and 10.8 kcal/mol-1 in PM7 to 3.8 kcal/mol-1. The origins of the errors in NDDO methods have been examined, and were found to be attributable to inadequate and inaccurate reference data. This conclusion provides insight into how these methods can be improved. © 2012 The Author(s).


Grant
Agency: Department of Health and Human Services | Branch: National Institutes of Health | Program: SBIR | Phase: Phase II | Award Amount: 458.29K | Year: 2015

Project Summary Abstract The rate of progress in developing new pharmaceuticals could be accelerated if experimental researchers had practical methods for modeling enzyme mechanisms Unfortunately all current programs have severe limitations either being too slow too complicated or too inaccurate Although an efficient and accurate method for modeling mechanisms in enzyme catalyzed reactions has been developed and made available in the form of the stand alone program MOPAC very few users of this program have used it for that purpose Instead most users have used it for modeling simpler systems such as the docking of substrates into active sites in enzymes This reluctance by experimentalists to model enzyme mechanisms can be attributed to the severe learning curve barrier currently necessary before useful results can be obtained Experimentalists want to focus on the chemistry involved and as far as possible do not want to become involved in computational details software requirements restrictions etc As a result tools that can be used efficiently by computational chemists are being essentially ignored by experimentalists despite the fact that if they were used they would be enormously valuable for modeling postulated reactions to determine their feasibility This project aims to reduce the size of this learning barrier by making MOPAC easier to use by developing documentation to describe what can be done the issues involved methods and strategies for exploring models of enzyme mechanisms and by providing several complete worked examples including the chymotrypsin catalyzed hydrolysis of a peptide bond The approach would begin with a small research project to map out the chymotrypsin mechanism Any software problems encountered would be addressed at this point Various strategies for exploring the mechanism would be examined and using the results a recommended set of procedures would be generated as documentation for use by experimentalists Experimentalists would then use the resulting program and documentation to model reactions and phenomena in systems of interest and their feedback would be used in improving the product A few cycles of modeling and feedback would yield a product that should be an acceptable tool for the experimental research community for modeling enzyme mechanisms Project Narrative The task of designing new pharmaceuticals can be aided by a computer assisted model of enzyme mechanism that would be easy to use A program to do this MOPAC already exists but currently it is only being used by expert computational chemists The objective is to modify the MOPAC program and its documentation to make it suitable for use by experimentalists


Grant
Agency: Department of Health and Human Services | Branch: | Program: SBIR | Phase: Phase I | Award Amount: 113.57K | Year: 2014

OCR issue PUBLIC HEALTH RELEVANCE Project Narrative The task of designing new pharmaceuticals can be aided by a computer-assisted model of enzyme mechanism that would be easy to use. A program to do this, MOPAC2012, already exists, but currently it is only being used by expert computational chemists. The objective is to modify the MOPAC2012 program and its documentation to make it suitable for use by experimentalists.


PubMed | Imperial College London, Center for Molecular Informatics and Stewart Computational Chemistry
Type: | Journal: Journal of cheminformatics | Year: 2015

The desirable curation of 158,122 molecular geometries derived from the NCI set of reference molecules together with associated properties computed using the MOPAC semi-empirical quantum mechanical method and originally deposited in 2005 into the Cambridge DSpace repository as a data collectionis reported.The procedures involved in the curation included annotation of the original data using new MOPAC methods, updating the syntax of the CML documents used to express the data to ensure schema conformance and adding new metadata describing the entries together with a XML schema transformation to map the metadata schema to that used by the DataCite organisation. We have adopted a granularity model in which a DataCite persistent identifier (DOI) is created for each individual molecule to enable data discovery and data metrics at this level using DataCite tools.We recommend that the future research data management (RDM) of the scientific and chemical data components associated with journal articles (the supporting information) should be conducted in a manner that facilitates automatic periodic curation. Graphical abstractStandards and metadata-based curation of a decade-old digital repository dataset of molecular information.

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