Automatic determination of reaction mappings and reaction center information. 2. Validation on a biochemical reaction database

The correct identification of the reacting bonds and atoms is a prerequisite for the analysis of the reaction mechanism. We have recently developed a method based on the Imaginary Transition State Energy Minimization approach for automatically determining the reaction center information and the atom-atom mapping numbers. We test here the accuracy of this ITSE approach by comparing the predictions of the method against more than 1500 manually annotated reactions from BioPath, a comprehensive database of biochemical reactions. The results show high agreement between manually annotated mappings and computational predictions (98.4%), with significant discrepancies in only 24 cases out of 1542 (1.6%). This result validates both the computational prediction and the database, at the same time, as the results of the former agree with expert knowledge and the latter appears largely self-consistent, and consistent with a simple principle. In 10 of the discrepant cases, simple chemical arguments or independent literature studies support the predicted reaction center. In five reaction instances the differences in the automatically and manually annotated mappings are described in detail. Finally, in approximately 200 cases the algorithm finds alternate reaction centers, which need to be studied on a case by case basis, as the exact choice of the alternative may depend on the enzyme catalyzing the reaction.     

Systematic analysis of enzyme-catalyzed reaction patterns and prediction of microbial biodegradation pathways

The roles of chemical compounds in biological systems are now systematically analyzed by high-throughput experimental technologies. To automate the processing and interpretation of large-scale data it is necessary to develop bioinformatics methods to extract information from the chemical structures of these small molecules by considering the interactions and reactions involving proteins and other biological macromolecules. Here we focus on metabolic compounds and present a knowledge-based approach for understanding reactivity and metabolic fate in enzyme-catalyzed reactions in a given organism or group. We first constructed the KEGG RPAIR database containing chemical structure alignments and structure transformation patterns, called RDM patterns, for 7091 reactant pairs (substrate-product pairs) in 5734 known enzyme-catalyzed reactions. A total of 2205 RDM patterns were then categorized based on the KEGG PATHWAY database. The majority of RDM patterns were uniquely or preferentially found in specific classes of pathways, although some RDM patterns, such as those involving phosphorylation, were ubiquitous. The xenobiotics biodegradation pathways contained the most distinct RDM patterns, and we developed a scheme for predicting bacterial biodegradation pathways given chemical structures of, for example, environmental compounds.     

Examining the robustness of first-principles calculations for metal hydride reaction thermodynamics by detection of metastable reaction pathways

First principles calculations have played a useful role in screening mixtures of complex metal hydrides to find systems suitable for H(2) storage applications. Standard methods for this task efficiently identify the lowest energy reaction mechanisms among all possible reactions involving collections of materials for which DFT calculations have been performed. The resulting mechanism can potentially differ from physical reality due to inaccuracies in the DFT functionals used, or due to other approximations made in estimating reaction free energies. We introduce an efficient method to probe the robustness of DFT-based predictions that relies on identifying reactions that are metastable relative to the lowest energy reaction path predicted with DFT. An important conclusion of our calculations is that in many examples DFT cannot unambiguously predict a single reaction mechanism for a well defined metal hydride mixture because two or more mechanisms have reaction energies that differ by a small amount. Our approach is illustrated by analyzing a series of single step reactions identified in our recent work that examined reactions with a large database of solids [Kim et al., Phys. Chem. Chem. Phys. 2011, 13, 7218].     

Large-scale screening of metal hydrides for hydrogen storage from first-principles calculations based on equilibrium reaction thermodynamics

Systematic thermodynamics calculations based on density functional theory-calculated energies for crystalline solids have been a useful complement to experimental studies of hydrogen storage in metal hydrides. We report the most comprehensive set of thermodynamics calculations for mixtures of light metal hydrides to date by performing grand canonical linear programming screening on a database of 359 compounds, including 147 compounds not previously examined by us. This database is used to categorize the reaction thermodynamics of all mixtures containing any four non-H elements among Al, B, C, Ca, K, Li, Mg, N, Na, Sc, Si, Ti, and V. Reactions are categorized according to the amount of H(2) that is released and the reaction's enthalpy. This approach identifies 74 distinct single step reactions having that a storage capacity >6 wt.% and zero temperature heats of reaction 15 ≤ΔU(0)≤ 75 kJ mol(-1) H(2). Many of these reactions, however, are likely to be problematic experimentally because of the role of refractory compounds, B(12)H(12)-containing compounds, or carbon. The single most promising reaction identified in this way involves LiNH(2)/LiH/KBH(4), storing 7.48 wt.% H(2) and having ΔU(0) = 43.6 kJ mol(-1) H(2). We also examined the complete range of reaction mixtures to identify multi-step reactions with useful properties; this yielded 23 multi-step reactions of potential interest.     

Model of the radical addition reaction as the superposition of three potential curves

A new semiempirical model of the reaction of radical addition to molecules with multiple bonds has been developed. In the framework of this model, the transition state (TS) of the reaction X^. + Y=Z → XYZ^. is considered as the result of the intersection of the potential curve of the stretching vibration of the forming bond X-Y with the curve that is the difference between the amplitudes of stretching vibrations of the Y-Z and Y=Z bonds and the stretching vibrations are considered harmonic. The kinetic parameters describing the activation energy as a function of the enthalpy of the reaction were calculated for 34 classes of addition reactions using the new model. The factors determining the activation energy of the addition reactions are analyzed: triplet repulsion in the TS, the π electrons in the α position to the reaction center, the electronegativity of atoms of the reaction center of the TS, the steric factor, the interaction of polar groups in the TS, and the force constants of the reacting bonds. The increments characterizing the contribution of these factors to the activation energy are calculated. The model is also used to describe the energy of 12 classes of cyclization reactions and 16 classes of radical decomposition reactions. The parameters that make it possible to estimate the activation energy of the reaction from its enthalpy are calculated for these classes of reactions.     

Stereochemically consistent reaction mapping and identification of multiple reaction mechanisms through integer linear optimization

Reaction mappings are of fundamental importance to researchers studying the mechanisms of chemical reactions and analyzing biochemical pathways. We have developed an automated method based on integer linear optimization, ILP, to identify optimal reaction mappings that minimize the number of bond changes. An alternate objective function is also proposed that minimizes the number of bond order changes. In contrast to previous approaches, our method produces mappings that respect stereochemistry. We also show how to locate multiple reaction mappings efficiently and determine which of those mappings correspond to distinct reaction mechanisms by automatically detecting molecular symmetries. We demonstrate our techniques through a number of computational studies on the GRI-Mech, KEGG LIGAND, and BioPath databases. The computational studies indicate that 99% of the 8078 reactions tested can be addressed within 1 CPU hour. The proposed framework has been incorporated into the Web tool DREAM ( http://selene.princeton.edu/dream/ ), which is freely available to the scientific community.     

MECHGEN: computer aided generation and reduction of reaction mechanisms

The paper describes selection rules implemented in a software generating "possible reaction mechanism", i.e. a set of elementary reactions chosen from all stoichiometrically possible reactions. The novelty of the approach lies in the fact that the user has to define all species involved (reactants, intermediates, products), and the rules applied with user-set limits reduce the resulting mechanism to a reasonable set of possible elementary reactions. The computer code consists of five parts: (i) definition of species, and introducing its characteristics (structure and thermodynamic data); (ii) definition of the reacting system and generation of all stoichiometrically possible reactions; (iii) reduction of the mechanisms using complexity and thermodynamic constraints based on user-set limits; (iv) calculation of the resulting pathways (routes of the various atoms or groups of atoms transferred from one species to another); and (v) tools to help visualization of the process by finding those elementary processes which realize a given pathway. Reasonable flexibility is ensured for using selection rules based on various criteria with limits set by the user. The various pathways are shown (in a matrix form), which offers an overview of the entire process.     

The dynamics of the C + PH3 reaction: a theoretical study

The C + PH(3) reaction is one of the simplest gas-phase processes which can produce molecular species containing P-C bonds. It could be of astrophysical importance and a reference for other phosphine reactions with carbon-containing molecular radicals. The dynamical aspects have been studied theoretically by quasi-classical trajectory methods in order to determine its rate as a function of the temperature, the branching ratios, and the molecular mechanisms. We have obtained a T(0.2) dependence of the capture rate. The total rate is affected by the existence of relatively high-lying saddle points for the isomerization of the CPH(3) complex but get a value of 0.82·10(-10) cm(3) s(-1) at 300 K, which is considered quite high for a neutral-neutral reaction and higher than those of similar reactions. Moreover, the total rate presents a weak dependence with the temperature. Our results indicate that several products containing P-C bonds are formed, the main reaction channel being the generation of HPCH + H.     

Enabling the exploration of biochemical pathways

The Biochemical Pathways Wall Chart (http://www.expasy.org/tools/pathways/ref.1) has been converted into a molecule and reaction database. Major features of this database are that each molecule is represented by lists of all atoms and bonds (as connection tables), and in the reactions the reaction centre, the atoms and bonds directly involved in the bond rearrangement process, are marked. The information in the database has been enriched by a set of diverse 3D structure conformations generated by the programs CORINA and ROTATE. The web-based structure and reaction retrieval system C@ROL provides a wide range of search methods to mine this rich database. The database is accessible at http://www2.chemie.uni-erlangen.de/services/biopath/index.html and http://www.mol-net.de/databases/biopath.html .     

π-Orbital electron–energy contributions to chemical reaction heats,I. Reactions involving only linear molecules containing up to three first–row atoms

Ab initio calculations of various expectation energies have been made for the reactant and product species in six reactions that involve only small linear molecules. The reactions include fission by hydrogen, addition of hydrogen, exchange of triply bonded atoms, fluorination, and oxygen atom transfer. The change in total electronic energy is not invariably the result of changes in inner shell energy and outer shell σ- and π-electron energies simply augmenting each other, but in several cases there is a complex interplay of opposing effects. This approach gives a different insight into the energetic aspects of changes in bonding from that derived from the concept of shared electron pairs in σ and π bonds together with lone pairs in valence shells. Changes in π-electron energy are shown to be important in a reaction in which neither reactant nor product molecules contain π bonds in the usual chemical sense. While in a reaction in which there is a complete change in the nature of the triple bonds, and hence the π bonding, the change in π-electron energy makes a smaller contribution than either the change in inner shell or the outer shell σ-electron energies.     

Blends of bisphenol a polycarbonate and acrylic polymers. I. A chemical reaction mechanism

The chemical reaction at high temperature (above 200°C) between PC and PMMA has been very recently highlighted. However, no clear reaction mechanism has been proposed to explain this phenomenon. We suggest a reaction mechanism following two steps. The first step consists of hydrolysis of the ester bonds of the PMMA leading to acid pendant groups. These acids can then either ring close into glutaric anhydride, or acidolyze the carbonate bonds of PC during the second step. At the same time, benzoic acid produced by PC degradation could further react with PMMA or acidolyze the carbonate groups leading to the crosslinking of the system. A satisfactory contact between the reacting units is a key point in the proces. Significant amounts of PC-PMMA copolymer are obtained when the reaction is performed from a miscible system. On the contrary, no reaction occurs during melt mixing. Understanding the process enables us to specify the conditions, in which no chemical reaction takes place. In nonreactive conditions, PC/PMMA blends remain immiscible for several hours at 300°C. The thermodynamic UCST proposed in the literature is just an artifact due to the occurrence of the chemical reaction. © 1995 John Wiley & Sons, Inc.     

Theory of reversible associative-dissociative diffusion-influenced chemical reaction. I. Geminate reaction

A many-particle, in the general case, inhomogeneous reacting system of independent pairs of reactants, where geminate reversible reaction A+B?C takes place, is considered in the framework of the kinetic theory approach. The kinetic equations in the thermodynamic limit are obtained, and important relations between kinetic coefficients characterizing the reaction course are established, as well as the relations between the kinetic dependencies under different initial conditions including the relations that extend the familiar literature results to the case of rather realistic model of the reacting system. Universal long-term kinetic laws of the reaction course are determined.     

A new approximate method for the stochastic simulation of chemical systems: the representative reaction approach

We have developed two new approximate methods for stochastically simulating chemical systems. The methods are based on the idea of representing all the reactions in the chemical system by a single reaction, i.e., by the “representative reaction approach” (RRA). Discussed in the article are the concepts underlying the new methods along with flowchart with all the steps required for their implementation. It is shown that the two RRA methods {with the reaction as the representative reaction (RR)} perform creditably with regard to accuracy and computational efficiency, in comparison to the exact stochastic simulation algorithm (SSA) developed by Gillespie and are able to successfully reproduce at least the first two moments of the probability distribution of each species in the systems studied. As such, the RRA methods represent a promising new approach for stochastically simulating chemical systems. © 2011 Wiley Periodicals, Inc. J Comput Chem, 2012     

Enhancement of reaction specificity at interfaces

A realistic picture of a cell is that of a highly viscous, condensed gel-like substance, crowded with macromolecules that are mostly anchored to membranes and to intricate networks of cytoskeletal elements. Theoretical and experimental approaches to investigating crowding have not considered the role of diffusion through a crowded medium in affecting the selectivity and specificity of reactions. Such diffusion is especially important when one considers interfaces, where at least one reactant must move through the medium and reach the interface. Here, we address this issue by directly investigating how diffusion through a gel medium affects the competition between a single specific reaction and a large number of weak nonspecific interactions, a process that is typical of reactions occurring at interfaces. We present an approach for achieving orientation-controlled interactions based on the configuration-dependent diffusion rate of the reacting molecule through a gel medium. The effectiveness of the method is demonstrated by the high selectivity obtained both in the adsorption of DNA to a surface and in DNA hybridization to preadsorbed single-strand oligomer on a surface.     

Over 20 years of reaction access systems from MDL: a novel reaction substructure search algorithm

From REACCS, to MDL ISIS/Host Reaction Gateway, and most recently to MDL Relational Chemistry Server, a new product based on Oracle data cartridge technology, MDL's reaction database management and retrieval systems have undergone great changes. The evolution of the system architecture is briefly discussed. The evolution of MDL reaction substructure search (RSS) algorithms is detailed. This article mainly describes a novel RSS algorithm. This algorithm is based on a depth-first search approach and is able to fully and prospectively use reaction specific information, such as reacting center and atom-atom mapping (AAM) information. The new algorithm has been used in the recently released MDL Relational Chemistry Server and allows the user to precisely find reaction instances in databases while minimizing unrelated hits. Finally, the existing and new RSS algorithms are compared with several examples.     

ROBIA: a reaction prediction program

A reaction prediction program, ROBIA, has been developed. This interactive computer program predicts the products of organic reactions from the starting materials and the reaction conditions, on the basis of the selected transformations within its database. This mechanistic approach generates a large number of products, from which the most important are selected using filters and molecular modeling calculations. The procedure has been applied to the possible biosynthesis pathway of dolabriferol. [reaction: see text]     

Adapting the nudged elastic band method for determining minimum-energy paths of chemical reactions in enzymes

Optimization of reaction paths for enzymatic systems is a challenging problem because such systems have a very large number of degrees of freedom and many of these degrees are flexible. To meet this challenge, an efficient, robust and general approach is presented based on the well-known nudged elastic band reaction path optimization method with the following extensions: (1) soft spectator degrees of freedom are excluded from path definitions by using only inter-atomic distances corresponding to forming/breaking bonds in a reaction; (2) a general transformation of the distances is defined to treat multistep reactions without knowing the partitioning of steps in advance; (3) a multistage strategy, in which path optimizations are carried out for reference systems with gradually decreasing rigidity, is developed to maximize the opportunity of obtaining continuously changing environments along the path. We demonstrate the applicability of the approach using the acylation reaction of type A beta-lactamase as an example. The reaction mechanism investigated involves four elementary reaction steps, eight forming/breaking bonds. We obtained a continuous minimum energy path without any assumption on reaction coordinates, or on the possible sequence or the concertedness of chemical events. We expect our approach to have general applicability in the modeling of enzymatic reactions with quantum mechanical/molecular mechanical models.     

Kinetic parameter estimation for 1,1,3,3-tetramethylguanidinum trifluoroacetate ionic liquid in the reaction of glycidyl methacrylate with carbon dioxide

The ionic liquid (IL) of 1,1,3,3-tetramethyl guanidinum trifluoroacetate, which was synthesized by reacting 1,1,3,3-tetramethylguanidine (TMG) and trifluoroacetic acid, was used as a catalyst of the reaction between carbon dioxide and glycidyl methacrylate (GMA)., The initial absorption rate of carbon dioxide into GMA solutions containing IL was measured in a semi-batch stirred tank with a plane gas-liquid interface at 101.3 kPa to obtain the reaction kinetics. The reaction rate constants of the reaction between carbon dioxide and GMA were evaluated from analysis of the mass transfer mechanism accompanied by the elementary reactions based on the film theory. Solvents such as toluene,N-methyl-2-pirrolidinone and dimethyl sulfoxide affected the reaction rate constants.     

Reaction of diisocyanates with alcohols. I. Uncatalyzed reactions

Because diisocyanates are widely used raw materials in the production of urethane elastomers and foams, it is of particular interest, to know the contribution of secondary reactions to the overall reaction between diisocyanates and polyether glycols, because of the well known influence of crosslinks on the physicochemical properties of polyurethanes. A mathematical method is suggested to calculate rate constants for the primary and secondary reactions, the hypothesis being that the allophanate group is the main secondary product. The method has been verified with experimental data obtained by reacting models. In addition, the influence of the [NCO]/[OH] ratio and of temperature on the formation of the allophanate group has been studied. The method has been applied to the reaction of 4,4′-diphenylmethane diisocyanate with poly(oxytetramethylene) glycol, a polyether glycol specifically designed for use in preparing polyurethanes. The results are in complete agreement with the experimental data.