KiSThelP: A program to predict thermodynamic properties and rate constants from quantum chemistry results†

Kinetic and Statistical Thermodynamical Package (KiSThelP) is a cross‐platform free open‐source program developed to estimate molecular and reaction properties from electronic structure data. To date, three computational chemistry software formats are supported (Gaussian, GAMESS, and NWChem). Some key features are: gas‐phase molecular thermodynamic properties (offering hindered rotor treatment), thermal equilibrium constants, transition state theory rate coefficients (transition state theory (TST), variational transition state theory (VTST)) including one‐dimensional (1D) tunnelling effects (Wigner, and Eckart) and Rice‐Ramsperger‐Kassel‐Marcus (RRKM) rate constants, for elementary reactions with well‐defined barriers. KiSThelP is intended as a working tool both for the general public and also for more expert users. It provides graphical front‐end capabilities designed to facilitate calculations and interpreting results. KiSThelP enables to change input data and simulation parameters directly through the graphical user interface and to visually probe how it affects results. Users can access results in the form of graphs and tables. The graphical tool offers customizing of 2D plots, exporting images and data files. These features make this program also well‐suited to support and enhance students learning and can serve as a very attractive courseware, taking the teaching content directly from results in molecular and kinetic modelling. © 2013 Wiley Periodicals, Inc.     

典型燃料点火延迟时间的一阶和二阶局部和全局敏感度分析

Sensitivity analysis is an important tool in model validation and evaluation that has been employed extensively in the analysis of chemical kinetic models of combustion processes. The input parameters of a chemical kinetic model are always associated with some uncertainties, and the effects of these uncertainties on the predicted combustion properties can be determined through sensitivity analysis. In this work, first- and second-order global and local sensitivity coefficients of ignition delay time with respect to the scaling factor for reaction rate constants in chemical kinetic mechanisms for combustion of H₂, methane, n-butane, and n-heptane are examined. In the sensitivity analysis performed here, the output of the model is taken to be natural logarithm of ignition delay time and the input parameters are the natural logarithms of the factors that scale the reaction rate constants. The output of the model is expressed as a polynomial function of the input parameters, with up to coupling between two input parameters in the present sensitivity analysis. This polynomial function is determined by varying one or two input parameters, and allows the determination of both local and global sensitivity coefficients. The order of the polynomial function in the present work is four, and the factor that scales the reaction rate constant is in the range from 1/e to e, where e is the base of the natural logarithm. A relatively small number of sample runs are required in this approach compared to the global sensitivity analysis based on the highly dimensional model representation method, which utilizes random sampling of input (RS-HDMR). In RS-HDMR, sensitivity coefficients are determined only for the rate constants of a limited number of reactions; the present approach, by contrast, affords sensitivity coefficients for a larger number of reactions. Reactions and reaction pairs with the largest sensitivity coefficients are listed for ignition delay times of four typical fuels. Global sensitivity coefficients are always positive, while local sensitivity coefficients can be either positive or negative. A negative local sensitivity coefficient indicates that the reaction promotes ignition, while a positive local sensitivity coefficient suggests that the reaction actually suppresses ignition. Our results show that important reactions or reaction pairs identified by global sensitivity analysis are usually rather similar to those based on local sensitivity analysis. This finding can probably be attributed to the fact that the values of input parameters are within a rather small range in the sensitivity analysis, and nonlinear effects for such a small range of parameters are negligible. It is possible to determine global sensitivity coefficients by varying the input parameters over a larger range using the present approach. Such analysis shows that correlation effects between an important reaction and a minor reaction can have relatively sizable second-order sensitivity coefficient in some cases. On the other hand, first-order global sensitivity coefficients in the present approach will be affected by coupling between two reactions, and some results of the first-order global sensitivity analysis will be different from those determined by local sensitivity analysis or global sensitivity analysis under conditions where the correlation effects of two reactions are neglected. The present sensitivity analysis approach provides valuable information on important reactions as well as correlated effects of two reactions on the combustion characteristics of a chemical kinetic mechanism. In addition, the analysis can also be employed to aid global sensitivity analysis using RS-HDMR, where global sensitivity coefficients are determined more reliably.     

pyEFP: Automatic decomposition of the complex molecular systems into rigid polarizable fragments

We present an open source tool able to describe intermolecular electrostatic interactions within the framework of the effective fragment potential (EFP) method. Complex molecular structure is subdivided into compact rigid fragments and parameters of their interactions are obtained from ab initio calculations. Automatic procedure allows for searching of these parameters into the existing database and merge new fragments into it. A set of standard fragments useful for the studies of organic semiconductors is also provided. Input files both for purely EFP and hybrid QM/MM calculations can be generated. The program is written in python and freely available on GitHub: https://github.com/ale-odinokov/pyEFP © 2017 Wiley Periodicals, Inc.     

The Chemistry Development Kit (CDK): an open-source Java library for Chemo- and Bioinformatics

The Chemistry Development Kit (CDK) is a freely available open-source Java library for Structural Chemo- and Bioinformatics. Its architecture and capabilities as well as the development as an open-source project by a team of international collaborators from academic and industrial institutions is described. The CDK provides methods for many common tasks in molecular informatics, including 2D and 3D rendering of chemical structures, I/O routines, SMILES parsing and generation, ring searches, isomorphism checking, structure diagram generation, etc. Application scenarios as well as access information for interested users and potential contributors are given.     

molSimplify: A toolkit for automating discovery in inorganic chemistry

We present an automated, open source toolkit for the first‐principles screening and discovery of new inorganic molecules and intermolecular complexes. Challenges remain in the automatic generation of candidate inorganic molecule structures due to the high variability in coordination and bonding, which we overcome through a divide‐and‐conquer tactic that flexibly combines force‐field preoptimization of organic fragments with alignment to first‐principles‐trained metal‐ligand distances. Exploration of chemical space is enabled through random generation of ligands and intermolecular complexes from large chemical databases. We validate the generated structures with the root mean squared (RMS) gradients evaluated from density functional theory (DFT), which are around 0.02 Ha/au across a large 150 molecule test set. Comparison of molSimplify results to full optimization with the universal force field reveals that RMS DFT gradients are improved by 40%. Seamless generation of input files, preparation and execution of electronic structure calculations, and post‐processing for each generated structure aids interpretation of underlying chemical and energetic trends. © 2016 Wiley Periodicals, Inc.     

Evolution of a Constitutional Dynamic Library Driven by Self‐Organisation of a Helically Folded Molecular Strand

Conversion of macrocyclic imine entities into helical strands was achieved through three‐ and four‐component exchange reactions within constitutionally dynamic libraries. The generation of sequences of the intrinsic helicity codon, based on the hydrazone–pyrimidine fragment obtained by condensation of pyrimidine dialdehyde A with pyrimidine bis‐hydrazine B , shifted the equilibrium between all the possible macrocycles and strands towards the full expression (>98%) of helical product [ A / B ]. Furthermore, it was shown that chain folding accelerated the dynamic exchange reactions among the library members. Lastly, in four‐component experiments (involving A , B , E and either C or D ), even though the macrocyclic entities ([ A / C ], [ B / E ]; [ A / D ], [ B / E ]) were the kinetically preferred products, over time dialdehyde A relinquished its initial diamine partners C or D to opt for bis‐hydrazine B , which allowed the preferential formation of the helically folded strand. The present results indicate that self‐organisation pressure was able to drive the dynamic system towards the selective generation of the strand undergoing helical folding.     

Computational approach to structural identification of phospholipids using raw mass spectra from nanoflow liquid chromatography–electrospray ionization–tandem mass spectrometry

A qualitative analysis tool (LiPilot) for identifying phospholipids (PLs), including lysophospholipids (LPLs), from biological mixtures is introduced. The developed algorithm utilizes raw data obtained from nanoflow liquid chromatography–electrospray ionization–tandem mass spectrometry experiments of lipid mixture samples including retention time and m/z values of precursor and fragment ions from data‐dependent, collision‐induced dissociation. Library files based on typical fragmentation patterns of PLs generated with an LTQ‐Velos ion trap mass spectrometer are used to identify PL or LPL species by comparing experimental fragment ions with typical fragment ions in the library file. Identification is aided by calculating a confidence score developed in our laboratory to maximize identification efficiency. Analysis includes the influence of total ion intensities of matched and unmatched fragment ions, the difference in m/z values between observed and theoretical fragment ions, and a weighting factor used to differentiate regioisomers through data filtration. The present study focused on targeted identification of particular PL classes. The identification software was evaluated using a mixture of 24 PL and LPL standards. The software was further tested with a human urinary PL mixture sample, with 93 PLs and 22 LPLs identified. Copyright © 2012 John Wiley & Sons, Ltd.     

Pteros: Fast and easy to use open‐source C++ library for molecular analysis

An open‐source Pteros library for molecular modeling and analysis of molecular dynamics trajectories for C++ programming language is introduced. Pteros provides a number of routine analysis operations ranging from reading and writing trajectory files and geometry transformations to structural alignment and computation of nonbonded interaction energies. The library features asynchronous trajectory reading and parallel execution of several analysis routines, which greatly simplifies development of computationally intensive trajectory analysis algorithms. Pteros programming interface is very simple and intuitive while the source code is well documented and easily extendible. Pteros is available for free under open‐source Artistic License from http://sourceforge.net/projects/pteros/ . © 2012 Wiley Periodicals, Inc.     

ReaxFF MD局部区域反应追踪与物理性质可视化分析

Recently, the application of ReaxFF based reactive molecular dynamics simulation (ReaxFF MD) in complex processes of pyrolysis, oxidation and catalysis has attracted considerable attention. The analysis of the simulation results of these processes is challenging owing to the complex chemical reactions involved, coupled with their dynamic physical properties. VARxMD is a leading tool for the chemical reaction analysis and visualization of ReaxFF MD simulations, which allows the automated analysis of reaction sites to get overall reaction lists, evolution trends of reactants and products, and reaction networks of specified reactants and products. The visualization of the reaction details and dynamic evolution profiles are readily available for each reactant and product. Additionally, the detailed reaction sites of bond breaking and formation are available in 2D chemical structure diagrams and 3D structure views; for specified reactions, they are categorized on the basis of the chemical structures of the bonding sites or function groups in the reacting species. However, the current VARxMD code mainly focuses on global chemical reaction information in the simulation system of the ReaxFF MD, and is incapable of locally tracking the chemical reaction and physical properties in a 3D picked zone. This work extends the VARxMD from global analysis to a focused 3D zone picked interactively from the 3D visualization modules of VARxMD, as well as physical property analysis to complement reaction analysis. The analysis of reactions and physical properties can be implemented in three steps: picking and drawing a 3D zone, identifying molecules in the picked zone, and analyzing the reactions and physical properties of the picked molecules. A 3D zone can be picked by specifying the geometric parameters or drawing on a screen using a mouse. The picking of a cuboid or sphere was implemented using the VTK 3D view libraries by specifying geometric parameters. The interactive 3D zone picking was implemented using a combination of observer and command patterns in the VTK visualization paradigm. The chemical reaction tracking and dynamic radial distribution function (RDF) of the 3D picked zone was efficiently implemented by inheriting data obtained from the global analysis of VARxMD. The reaction tracking between coal particles in coal pyrolysis simulation and dynamic structure characterization of carbon rich cluster formation in the thermal decomposition of an energetic material are presented as application examples. The obtained detailed reactions between the coal particles and comparison of the reaction between the locally and globally picked areas in the cuboid are helpful in understanding the role of micro pores in coal particles. The carbon to carbon RDF analysis and comparison of the spherical region picked for the layered molecular clusters in the pyrolysis system of the TNT crystal model with the standard RDF of the 5-layer graphene demonstrate the extended VARxMD as a chemical structure characteristic tool for detecting the dynamic formation profile of carbon rich clusters in the pyrolysis of TNT. The extended capability of VARxMD for a 3D picked zone of a ReaxFF MD simulation system can be useful for interfacial reaction analysis in a catalysis system, hot spot formation analysis in the detonation of energetic material systems, and particularly the pyrolysis or oxidation processes of coal, biomass, polymers, hydrocarbon fuels, and energetic materials.     

MoCalc: a new graphical user interface for molecular calculations

A new computer program called MoCalc (Molecular Calculations) has been designed to help the computational chemistry practitioner in the task of performing and analyzing molecular calculations. MoCalc is a graphical user interface for the MO calculation programs Gamess and Mopac, and uses Rasmol and Babel for molecule display and file conversion, respectively. In its initial version, MoCalc can execute the following operations: (a) create and handle Gamess and Mopac input files; (b) import any kind of molecular geometry supported by Babel and paste it as Cartesian, internal, or Gaussian-type coordinates on the input file; (c) convert Gamess and Mopac output files to inputs of both programs; (d) edit and validate the keywords that control the Gamess and Mopac calculation procedure; (e) display the input (Mopac) and output (Gamess and Mopac) molecular geometries; (f) run single or multiple (batch) calculations, either interactively or in background; (g) automatically open the output files as soon as the calculation finishes; (h) extract results from the output files, such as energy, charges, dipole, population analysis, wave function, bond orders, and valence analysis, and display them in spreadsheets; (i) calculate reactivity indices derived from the frontier orbital theory and the root-mean-square (rms) deviation of input and output geometries. All the results generated by MoCalc can be promptly transferred to text editors and electronic spreadsheets, which facilitate a detailed subsequent analysis and the publication of the results. MoCalc can also perform graphical and numerical comparative analysis of the some results when more than one output file is loaded. The program was coded in Visual Basic and runs in Windows 95/98/NT4/ME/2000/XP environments.     

Network visualization system for computational chemistry

Network Visualization System for Computational Chemistry (NVSCC) is a molecular graphics program designed for the visualization of molecular assemblies. NVSCC accepts the output files from the most popular ab initio quantum chemical programs, GAUSSIAN and GAMESS, and provides visualization of molecular structures based on atomic coordinates. The main differences between NVSCC and other programs are: Network support due to built-in FTP and telnet clients, which allows for the processing of output from and the sending of input to different computer systems and operating systems. The possibility of working with output files in real time mode. The possibility of animation from an output file during all steps of optimization. The quick processing of huge volumes of data. The development of custom interfaces.     

A new derivatization strategy for the analysis of phosphopeptides by precursor ion scanning in positive ion mode

Although numerous strategies have been devised to analyze protein phosphorylation, an abundant intracellular protein modification, there is still a need for different methods for the analysis of this modification. A method to both detect and localize the phosphorylation within a protein/peptide is especially required. In this paper, a new strategy is described, which makes use of beta-elimination/Michael addition reactions to introduce a functional group at the original site of phosphorylation, which gives rise to a dimethylamine-containing sulfenic acid derivative with a unique m/z value. This enables the detection of the phosphorylated species within peptide mixtures by sensitive and specific precursor ion scanning in positive ion mode. Working under acidic conditions in positive ion mode has the added advantage that subsequent normal peptide sequencing for the exact localization can be performed. No other peptide derived fragment ion is observed at the m/z value of the sulfenic acid derivative formed, thus specific precursor ion experiments can also be carried out on instruments with low fragment ion resolution and lends itself to LC-MS/MS approaches when skimmer fragmentation routines or triple quadrupole mass spectrometers are used.     

CCSfind: A tool for chemically informed LC-IM-MS database building

In addition to providing critical knowledge of the accurate mass of ions, ion mobility-mass spectrometry (IM-MS) delivers complementary data relating to the conformation and size of ions in the form of an ion mobility spectrum and derived parameters, namely, the ion's mobility (K) and the IM-derived collision cross section (CCS). However, the maximum amount of information obtained in IM-MS measurements is not currently transferred into analytical databases including the full mobility spectra (CCS distributions) as well as capturing of additional ion species (e.g., adducts) into the same compound entry. We introduce CCSfind, a new tool for building comprehensive databases from experimental IM-MS measurements of small molecules. CCSfind allows predicted ion species to be chosen for input chemical formulae, which are then targeted by CCSfind after parsing open source mzML input files to provide a unified set of results within a single data processing step. CCSfind can handle both chromatographically separated isomers and IM separation of isomeric ions (e.g., “protomers” or conformers of the same ion species) with simple user control over the output for new database entries in SQL format. Files of up to 1 GB can be processed in less than 2 min on a desktop computer with 32 GB RAM with computational time scaling linearly with the size of the input mzML file or the number of input molecular formulae. Results are manually reviewed, annotated with experimental settings, before committing the database where the full dataset can be retrieved.     

Automatic spike correction using UNIFIT 2020

The improvement of the software UNIFIT 2020 from an analysis processing software for photoelectron spectroscopy (XPS) only to a powerful tool for XPS, Auger electron spectroscopy (AES), X-ray absorption spectroscopy (XAS), and Raman spectroscopy requires new additional programme routines. Particularly, the implementation of the analysis of Raman spectra needs a well-working automatic spike correction. The application of the modified discrete Laplace operator method allows for a perfect localization and correction of the spikes and finally a successful peak fit of the spectra. The theoretical basis is described. Test spectra allow for the evaluation of the presented method. A comparison of the original and spike-corrected real measurements demonstrates the high quality of the method used.     

Design and Synthesis of 56 Shape-Diverse 3D Fragments

Fragment-based drug discovery is now widely adopted for lead generation in the pharmaceutical industry. However, fragment screening collections are often predominantly populated with flat, 2D molecules. Herein, we describe a workflow for the design and synthesis of 56 3D disubstituted pyrrolidine and piperidine fragments that occupy under-represented areas of fragment space (as demonstrated by a principal moments of inertia (PMI) analysis). A key, and unique, underpinning design feature of this fragment collection is that assessment of fragment shape and conformational diversity (by considering conformations up to 1.5 kcal mol⁻¹ above the energy of the global minimum energy conformer) is carried out prior to synthesis and is also used to select targets for synthesis. The 3D fragments were designed to contain suitable synthetic handles for future fragment elaboration. Finally, by comparing our 3D fragments with six commercial libraries, it is clear that our collection has high three-dimensionality and shape diversity.     

On‐Demand Production of Flow‐Reactor Cartridges by 3D Printing of Thermostable Enzymes

The compartmentalization of chemical reactions is an essential principle of life that provides a major source of innovation for the development of novel approaches in biocatalysis. To implement spatially controlled biotransformations, rapid manufacturing methods are needed for the production of biocatalysts that can be applied in flow systems. Whereas three‐dimensional (3D) printing techniques offer high‐throughput manufacturing capability, they are usually not compatible with the delicate nature of enzymes, which call for physiological processing parameters. We herein demonstrate the utility of thermostable enzymes in the generation of biocatalytic agarose‐based inks for a simple temperature‐controlled 3D printing process. As examples we utilized an esterase and an alcohol dehydrogenase from thermophilic organisms as well as a decarboxylase that was thermostabilized by directed protein evolution. We used the resulting 3D‐printed parts for a continuous, two‐step sequential biotransformation in a fluidic setup.     

ALADDIN: An integrated tool for computer-assisted molecular design and pharmacophore recognition from geometric,steric, and substructure searching of three-dimensional molecular structures

Summary ALADDIN is a computer program for the design or recognition of compounds that meet geometric, steric, and substructural criteria. ALADDIN searches a database of three-dimensional structures, marks atoms that meet substructural criteria, evaluates geometric criteria, and prepares a number of files that are input for molecular modification and coordinate generation as well as for molecular graphics. Properties calculated from the three-dimensional structure are described by either properties calculated from the molecule itself or from the molecule as compared to a reference molecule and associated surfaces. ALADDIN was used to design analogues to probe a bioactive conformation of a small molecule and a peptide, to test alternative superposition rules for receptor mapping of the D2 dopamine receptor, to recognize unexpected D2 dopamine agonist activity of existing compounds, and to design compounds to fit a binding site on a protein of known structure. We have found that series designed by ALADDIN show much more subtle variation in shape than do those designed by traditional methods and that compounds can be designed to be very close matches to the objective.     

TANGO: A high through-put conformation generation and semiempirical method-based optimization tool for ligand molecules

Lead optimization is one of the crucial steps in the drug discovery pipeline. After identifying the lead molecule and obtaining its 2D geometry, understanding the best conformation it would attain in 3D still remains one of the most challenging steps in drug discovery. There have been multiple methods and algorithms that are directed toward achieving best conformation for the lead molecules. TANGO focuses on conformation generation and its optimization using semiempirical energy calculations. The conformation generation is based on torsion angle rotation of the exocyclic bonds. The energy calculations are performed using MOPAC. The unique feature of this tool lies in the implementation of Message Passing Interface (MPI) for conformation generation and semiempirical-based optimization. A well-defined architecture handling the input and output generation has been used. The master and slave approach to handle operations involved in torsion angle rotation and energy calculations has helped in load balancing the process of conformation generation. The benchmarking results suggest that TANGO scales significantly well across eight nodes with each node utilizing 16 cores. This tool may prove to very useful in high throughput generation of semiempirically optimized small molecule conformations. The use of semiempirical methods for optimization generates a conformational ensemble thereby helping to obtain stable and alternate stable conformers for a given ligand molecule. © 2018 Wiley Periodicals, Inc.     

Total synthesis of laulimalide: synthesis of the northern and southern fragments

The first stage in the development of a synthetic route for the total synthesis of laulimalide (1) is described. Our retrosynthetic analysis envisioned a novel macrocyclization route to the natural product by using a Ru-catalyzed alkene-alkyne coupling. This would be preceded by an esterification of the C19 hydroxyl group, joining together two equally sized synthons, the northern fragment 7 and the southern fragment 8. Our first generation approach to the northern fragment entailed a key sequential Ru/Pd coupling sequence to assemble the dihydropyran. The key reactions proceeded smoothly, but the inability to achieve a key olefin migration led to the development of an alternative route based on an asymmetric dinuclear Zn-catalyzed aldol reaction of a hydroxyl acylpyrrole. This key reaction led to the desired diol adduct 66 with excellent syn/anti selectivity (10:1), and allowed for the successful completion of the northern fragment 7. The key step for the synthesis of the southern fragment was a chemoselective Rh-catalyzed cycloisomerization reaction to form the dihydropyran ring from a diyne precursor. This reaction proved to be selective for the formation of a six-membered ring, over a seven. The use of an electron-deficient bidentate phosphine allowed for the reaction to proceed with a reduced catalyst loading.     

NADA: A versatile PC based program for neutron activation data analysis

We have developed a PC based program for neutron activation data analysis using the FORTRAN and C languages. The routines are based on creating files associated with conventional ORTEC hardware and output software. The main features of the program include radionuclide identification, and the use of semi-automatic integration or the peak fitting SAMPO routine. Other developments are hard and soft copy records for detailed sample identification and particular irradiation, decay and counting procedures. Flux variations, high deadtime corrections, counting geometries, spectral and nuclear interferences, as well as uranium fission interferences are also automatically accounted for. The data output includes concentration values in %, ppm, g or ppb units with associated errors, while detection limits for each individual sample are indicated. Further data output can easily be generated which can be imported to most spreadsheet programs for various statistical uses. A future implementation to the program will include batch-file processing and automated self-absorption calculations for geological samples.