Under certain conditions, reactive chemicals may proceed into uncontrolled chemical reaction pathways with rapid and significant increases in temperature, pressure, and/or gas evolution. Reactive chemicals have been involved in many industrial incidents, and have harmed people, property, and the environment. Evaluation of reactive chemical hazards is critical to design and operate safer chemical plant processes. Much effort is needed for experimental techniques, mainly calorimetric analysis, to measure thermal reactivity of chemical systems. Studying all the various reaction pathways experimentally however is very expensive and time consuming. Therefore, it is essential to employ simplified screening tools and other methods to reduce the number of experiments and to identify the most energetic pathways. A systematic approach is presented for the evaluation of reactive chemical hazards. This approach is based on a combination of computational methods, correlations, and experimental thermal analysis techniques. The presented approach will help to focus the experimental work to the most hazardous reaction scenarios with a better understanding of the reactive system chemistry. Computational methods are used to predict reaction stoichiometries, thermodynamics, and kinetics, which then are used to exclude thermodynamically infeasible and non-hazardous reaction pathways. Computational methods included: (1) molecular group contribution methods, (2) computational quantum chemistry methods, and (3) correlations based on thermodynamic-energy relationships. The experimental techniques are used to evaluate the most energetic systems for more accurate thermodynamic and kinetics parameters, or to replace inadequate numerical methods. The Reactive System Screening Tool (RSST) and the Automatic Pressure Tracking Adiabatic Calorimeter (APTAC) were employed to evaluate the reactive systems experimentally. The RSST detected exothermic behavior and measured the overall liberated energy. The APTAC simulated near-adiabatic runaway scenarios for more accurate thermodynamic and kinetic parameters. The validity of this approach was investigated through the evaluation of potentially hazardous reactive systems, including decomposition of di-tert-butyl peroxide, copolymerization of styrene-acrylonitrile, and polymerization of 1,3-butadiene.

Under certain conditions, reactive chemicals may proceed into uncontrolled chemical reaction pathways with rapid and significant increases in temperature, pressure, and/or gas evolution. Reactive chemicals have been involved in many industrial incidents, and have harmed people, property, and the environment. Evaluation of reactive chemical hazards is critical to design and operate safer chemical plant processes. Much effort is needed for experimental techniques, mainly calorimetric analysis, to measure thermal reactivity of chemical systems. Studying all the various reaction pathways experimentally however is very expensive and time consuming. Therefore, it is essential to employ simplified screening tools and other methods to reduce the number of experiments and to identify the most energetic pathways. A systematic approach is presented for the evaluation of reactive chemical hazards. This approach is based on a combination of computational methods, correlations, and experimental thermal analysis techniques. The presented approach will help to focus the experimental work to the most hazardous reaction scenarios with a better understanding of the reactive system chemistry. Computational methods are used to predict reaction stoichiometries, thermodynamics, and kinetics, which then are used to exclude thermodynamically infeasible and non-hazardous reaction pathways. Computational methods included: (1) molecular group contribution methods, (2) computational quantum chemistry methods, and (3) correlations based on thermodynamic-energy relationships. The experimental techniques are used to evaluate the most energetic systems for more accurate thermodynamic and kinetics parameters, or to replace inadequate numerical methods. The Reactive System Screening Tool (RSST) and the Automatic Pressure Tracking Adiabatic Calorimeter (APTAC) were employed to evaluate the reactive systems experimentally. The RSST detected exothermic behavior and measured the overall liberated energy. The APTAC simulated near-adiabatic runaway scenarios for more accurate thermodynamic and kinetic parameters. The validity of this approach was investigated through the evaluation of potentially hazardous reactive systems, including decomposition of di-tert-butyl peroxide, copolymerization of styrene-acrylonitrile, and polymerization of 1,3-butadiene.

Chirality can be induced in achiral solvent molecules located near a chiral molecule or surface, but there have been very few systematic studies in this field either experimentally or theoretically. The focus of this thesis is to study the chirality transfer from chiral molecules to achiral solvents. To capture the chirality transfer in solvent molecules, a solvent model that is sensitive to the changes in the environment is needed. We developed new polarizable and flexible models based on an extensive series of ab initio calculations and molecular dynamics simulations. The models include electric field dependence in both the atomic charges and the intramolecular degrees of freedom. Modified equations of motion are required and we have implemented a multiple time step algorithm to solve these equations. Our methodology is general and has been applied to ethanol as a test. For other solvents in our simulations, such as 2-propanol, limited models are used. The chirality transfer from chiral solutes to achiral solvents and its dependence on the solute and solvent characteristics are then explored using the new polarizable models in molecular dynamics simulations. The chirality induced in the solvent is assessed based on a series of related chirality indexes originally proposed by Osipov[Osipov et al., Mol. Phys.84, 1193(1995)]. Two solvents are considered: Ethanol and benzyl alcohol. The solvation of three chiral solutes is examined: Styrene oxide, acenaphthenol, and n-(1-(4-bromophenyl)ethyl)pivalamide (PAMD). All three solutes have the possibility of hydrogen-bonding with the solvent, the last two may also form π-π interactions, and the last has multiple hydrogen bonding sites. The chirality transfer from chiral surfaces to achiral solvents is also explored. Emphasis is placed on the extent of this chirality transfer and its dependence on the surface and solvent characteristics is explored. Three surfaces employed in chiral chromatography are examined: The Whelk-O1 interface; a phenylglycine-derived chiral stationary phase (CSP); and a leucine-derived CSP. The solvents consist of ethanol, a binary n-hexane/ethanol solvent, 2-propanol, and a binary n-hexane/2-propanol solvent. Molecular dynamics simulations of the solvated chiral interfaces form the basis of the analysis and position dependent chirality indexes are analyzed in detail. / Thesis (Ph.D, Chemistry) -- Queen's University, 2009-09-24 00:25:15.174

No description available.

Zugl.: Tübingen, Univ., Diss., 2006

Zugl.: Frankfurt (Main), University, Diss., 2008.

<p> I used molecular dynamics (MD) simulations as a primary tool to study folding and dynamics of signaling and regulatory proteins. Specifically, I have studied two classes of proteins: the first part of my thesis reports studies on peptides and receptors of the insulin family, and the second part reports on studies of regulatory proteins from the G-protein coupled receptor family. The first problem that I investigated was understanding the folding mechanism of the insulin B-chain and its mimetic peptide (S371) which were studied using enhanced sampling simulation methods. I validated our simulation approaches by predicting the known solution structure of the insulin B-chain helix and then applied them to study the folding of the mimetic peptide S371. Potentials of mean force (PMFs) along the reaction coordinate for each peptide are further resolved using the metadynamics method. I further proposed receptor-bound models of S371 that provide mechanistic explanations for competing binding properties of S371 and a tandem hormone-binding element of the receptor known as the C-terminal (CT) peptide. Next, I studied the all-atom structural models of peptides containing 51 residues from the transmembrane regions of IR and the type-1 insulin-like growth factor receptor (IGF1R) in a lipid membrane. In these models, the transmembrane regions of both receptors adopt helical conformations with kinks at Pro961 (IR) and Pro941 (IGF1R), but the C-terminal residues corresponding to the juxta-membrane region of each receptor adopt unfolded and flexible conformations in IR as opposed to a helix in IGF1R. I also observe that the N-terminal residues in IR form a kinked-helix sitting at the membrane-solvent interface, while homologous residues in IGF1R are unfolded and flexible. These conformational differences result in a larger tilt-angle of the membrane-embedded helix in IGF1R in comparison to IR to compensate for interactions with water molecules at the membrane-solvent interfaces. The metastable/stable states for the transmembrane domain of IR, observed in a lipid bilayer, are consistent with a known NMR structure of this domain determined in detergent micelles, and similar states in IGF1R are consistent with a previously reported model of the dimerized transmembrane domains of IGF1R. I further studied dimerization propensities of IR transmembrane domains using three different constructs in a lipid bilayer (isolated helices, ectodomain-anchored helices, and kinase-anchored helices). These studies revealed that the transmembrane domains can dimerize in isolation and in kinase-anchored forms, but not significantly in the ectodomain construct. The final studies in my thesis are focused on interplay of protein dynamics and small-molecule inhibition in a set of regulatory proteins known as the Regulators of G-protein Signaling (RGS) proteins. Thiadiazolidinone (TDZD) compounds have been shown to inhibit the protein-protein interaction between RGS and the alpha subunit of G-proteins by covalent modification of cysteine residues in RGS proteins. However, some of these cysteines in RGS proteins are not surface-exposed. I hypothesized that transient binding pockets expose cysteine residues differentially between different RGS isoforms. To explore this hypothesis, long time-scale classical MD simulations were used to probe the dynamics of three RGS proteins (RGS4, RGS8, and RGS19), and characterize flexibility in various helical motifs. The results from simulation studies were validated by hydrogen-deuterium exchange (HDX) studies, and revealed motions indicating solvent exposure of buried cysteine residues, thereby providing insights into inhibitor binding mechanisms. In addition, I used different published HDX models which have resulted in a comprehensive comparison of existing models. Furthermore, I developed the new HDX models with optimized parameters which had comparable accuracy and more computational efficiency compared to other models. Overall, my thesis has resulted in the development and applications of several state-of-the-art computational methods that have provided a detailed mechanistic understanding of peptide and small-molecule based inhibitors and their interactions with large proteins that are potentially useful in designing novel approaches to target protein-protein interactions. </p><p>

Iron containing metalloenzymes are an extremely important class of biocatalysts conserved throughout evolution because of their vital role in the biochemistry of life. Here we discuss a specific class of these enzymes that use molecular oxygen binding to enable there activity. We also attempt to describe synthetic analogues whose chemistry is based on that seen in those natural systems. This dissertation will highlight how computational research can illuminate specific aspects of the reaction mechanisms that these systems catalyse, which in many cases are unable to be understood purely experimentally. We report on two combined QM/MM and density functional theory (DFT) projects, which describe the AlkB demethylation enzyme and the SyrB2 halogenase; both highlight the strengths and weaknesses of each method. Our DFT work on an i-propyl-bis(imino)pyridine, an equatorial tridentate ligand, developed by one of the papers’ co-authors (Badiei, Siegler et al. 2011) exampifies superoxo chemistry based on the dioxygenases. Our other projects focus on monooxygenase catalysed chemistry one based on the biomimic [FeIV(O)(TPA)Cl]+ reports on a halogenase mimic that shows exciting chemoselectivity in halogenation vs. hydroxylation. I also report on publications examining two other biomimetic ligands. A imido-bridged diiron-oxo phtalocyanine complex capable of hydroxylating methane and a nonheme iron system which gives us a good deal of insight into the effects of secondary coordination sphere chemistry [FeII(N4Py2Ph)(NCCH3)](BF4)2. My computational studies have given insight into the chemical properties of metal-oxo oxidants and their reactivity patterns with substrate and have been utilized to explain experimentally observed data.

In this study, the novel, reaction energy profile-fragment attributed molecular system energy change (REP-FAMSEC) was applied in studying mechanisms of chemical reactions. The applicability of the REP-FAMSEC protocol was tested for the mechanism of proline catalysed aldol reaction whereby several possible mechanisms have been debated for the past four decades. The approach quantifies and explains energy changes for each successive step along with the reaction profile. It mainly uses interaction energies between meaningful polyatomic fragments of a molecular system and generates energy contribution made by each fragment of a molecule. The fragments or atoms driving or opposing a change can easily be discovered and the reason for their (un)reactivity can be established. The relative stability and catalytic behaviour of (S) proline conformers including the zwitterion were fully explained at an atomic and molecular level. Though the zwitterion becomes the most dominant conformer in dimethyl sulfoxide (DMSO) solvent, it is not the active catalyst in proline catalysis. It forms very weak interactions with the ketone donor and will not form the active enamine catalyst. The study shows that the first step of the catalytic reaction which was coined as the C–N bond formation using classical techniques, cannot be explained using the interaction of the N–,C+ atom pair but rather by the interaction of O-atom of acetone and the acidic H-atom of proline. Hence the first step is best described as the C–N bond formation/1st H-transfer. Based on this initial interaction the lowest energy conformer of proline is eliminated as a catalyst. When the REP is explored in the presence of an explicit solvent molecule of DMSO, FAMSEC shows that molecules of proline conformers (lowest 1a and higher energy 1b), acetone 2, and DMSO 3 are involved in strong intermolecular interactions when they form 3-molecular complexes (3-MCs). The interactions formed by the molecule of DMSO weaken interactions between 1a and 2 while strengthening those between 1b and 2, thereby eliminating 1a as an inactive catalyst. The zwitterion which becomes the most dominant in DMSO is converted to conformer 1a through a low energy barrier intramolecular proton transfer. When formed conformer 1a undergoes a puckering of the pyrrolidine ring resulting in its conversion to the catalytically active conformer 1b. The presence of a molecule of acetone, DMSO, or a combination of the two molecules facilitates the structural change of proline from conformer 1a to 1b. This shows that there is no need to adhere to a specific sequence of reagent addition in proline catalysis. During the formation of the active enamine catalyst from an initial imine, it was found that the molecule of the eliminated water acts as a medium for proton transfer relay while interaction involving the solvent molecule of DMSO is essential for decreasing the energy barrier and stabilising the resulting enamine catalyst. / Thesis (PhD)--University of Pretoria, 2020. / Chemistry / PhD / Unrestricted

Since the development of the correlation consistent composite approach (ccCA) in 2006, ccCA has been shown to be applicable across the periodic table, producing, on average, energetic properties (e.g., ionization potentials, electron affinities, enthalpies of formation, bond dissociation energies) within 1 kcal/mol for main group compounds. This dissertation utilizes ccCA in the investigation of several chemical systems including nitrogen-containing compounds, sulfur-containing compounds, and carbon dioxide complexes. The prediction and calculation of energetic properties (e.g., enthalpies of formation and interaction energies) of the chemical systems investigated within this dissertation has led to suggestions of novel insensitive highly energetic nitrogen-containing compounds, defined reaction mechanisms for sulfur compounds allowing for increased accuracy compared to experimental enthalpies of formation, and a quantitative structure activity relationship for altering the affinity of CO2 with substituted amine compounds. Additionally, a study is presented on the convergence of correlation energy and optimal domain criteria for local Møller–Plesset theory (LMP2).