Detailed chemical kinetic models are important to the understanding and prediction of combustion properties. Better estimations require an accurate description of thermochemistry and kinetic rate parameters. This study identifies important reaction pathways at the low temperature chemistry of branched conventional and alternative fuels. Rate constants and branching ratios for important reactions are provided and important phenomena are investigated. The thermochemistry and kinetics of the 2-methylhexane model, an important component in gasoline surrogate, is updated using recent group values and rate rules from the literature. New reactions, such as hydroperoxyalkylperoxy (OOQOOH) alternative isomerization, are also added to the model. The results show that both conventional and alternative isomerization of OOQOOH radicals significantly affect the model reactivity. The kinetics of a biofuel; iso-butanol, is also investigated in this study to understand alcohol combustion chemistry and identify sensitive reactions that require more attention. The results indicate that iso-butanol is sensitive to the chain propagation reaction of α-RO2 radical and the water elimination of γ-QOOH. Because both reactions decrease model reactivity, accurate rate constants are needed to correctly determine fuel reactivity. In light of the above mentioned kinetic modeling studies, high levels computational chemistry calculations were performed to provide site-specific rates rules for OOQOOH conventional isomerization considering all possible reaction sites. This is also one of the first studies to investigate the effect of chirality on calculated rate constants. Results indicate that chirality is important when two chiral centers exist in the reactant. OOQOOH alternative isomerization rate constants are usually assigned in analogy to the isomerization of an alkylperoxy (RO2) radical which may introduce some uncertainty. To test the validity of using analogous rates, this study calculates the rate constants for selected alternative isomerization reactions. The effect of intramolecular hydrogen bonding in the calculated energies and rate constants for different reaction pathways is investigated. The result shows that alternative isomerization is a competing pathway only when it proceeds via a less strained transition state relative to the conventional isomerization transition state. A detailed analysis of the hydrogen bonding effect helped to identify cases where assigning rates in analogy may not be valid.

The primary focus of this work is the investigation into the nature and origin of the electron density between the ortho-hydrogens in the higher energy, planar transition state of biphenyl. This interaction has been the subject of debate within the scientific community for almost three decades with no clear consensus being made. Since the distance between these hydrogens is smaller than their summed van der Waals radii (2.4 Å), classically one can assume that they partake in a steric clash, however the Quantum Theory of Atoms in Molecules (QTAIM) depicts a bond path for this H,H contact. This presence of a bond path caused the rift in the scientific community. To investigate the problem, we made use of cross-section decomposition analysis whereby the electron density at any given coordinate is decomposed into the components that contribute to its presence. In this dissertation, three methods using this analysis were made, namely (i) MO-ED, (ii) FALDI-ED, and (iii) NBO-ED. These represent the decomposition products that the density is decomposed into; the MO-ED method decomposed the density between the ortho-hydrogens into its molecular orbital (MO) contributions, the FALDI-ED method decomposed the density into fragment and diatomic contributions, and the NBO-ED method decomposed the density into its natural bond orbital (NBO) contributions. With all three methods, when decomposing the density along eigenvector-2 from the bond critical point (BCP) between the ortho-hydrogens in the planar conformer, it was found that the total electron density is concentrating, shown by the directional second partial derivative. This means that the electron density is purposefully accumulated in the H,H contact rather than dissipated as one would expect from a classical steric clash. Furthermore, this density decomposition analysis revealed that this density is due to a large molecular-wide delocalisation, rather than a classical 2-centred approach, with the largest contributions (in both conformers) being from the two covalent ortho C-H bonds. This delocalisation forms a density channel between two hydrogens, of an overwhelmingly concentrating/bonding nature, forming a weak covalent bond. Due to these findings, it is clear that the classical idea of a steric clash cannot be the case for this system, and that QTAIM correctly predicts the bond path between these ortho-hydrogens. / Dissertation (MSc (Chemistry))--University of Pretoria, 2021. / Chemistry / MSc (Chemistry) / Unrestricted

Bakterielle und parasitäre MIP-Proteine stellen wichtige Virulenzfaktoren dar, deren Inhibition das Überleben der Erreger sowie deren Penetration in menschliche Zellen stark einschränken kann. In dieser Arbeit standen die MIP-Proteine von Burkholderia pseudomallei (Auslöser der Melioidose) und Legionella pneumophila (Legionärskrankheit) im Fokus. Außerdem wurde das MIP-Protein von Trypanosoma cruzi (Chagas-Krankheit) untersucht. Die strukturverwandten humanen FKB-Proteine FKBP12 und FKBP52 sind relevante „off-targets“, wie Experimente mit Knockout-Mäusen gezeigt haben. Ziel dieser Arbeit war die Verbesserung von bekannten MIP-Inhibitoren im Hinblick auf ihre Affinität und Selektivität für MIP-Proteine gegenüber den beiden genannten FKB-Proteinen bei gleichzeitig verbesserter Löslichkeit, mit Hilfe von in silico Methoden. Ausgangspunkt waren hierbei zwei von Dr. Christina Juli und Dr. Florian Seufert entwickelte Leitstrukturen, welche ein Pipecolinsäuregrundgerüst aufweisen. Diese Referenzliganden beinhalten einen 3,4,5-Trimethoxyphenylring (TMPR, vgl. Ref_t) bzw. einen Pyridinylring (Ref_p). Beim Vergleich von insgesamt 32 MIP- und FKB-Proteinen konnten in zwei Loop-Bereichen, welche 50er bzw. 80er Loop genannt werden, relevante Unterschiede in der Aminosäuresequenz identifiziert werden. Die Nummerierung bezieht sich stets auf FKBP12. Diese Unterschiede ließen sich zum Design von vergleichsweise selektiv an MIP-Proteine bindenden Molekülen nutzen. Der 50er Loop ist in nahezu allen MIP-Proteinen (jedoch nicht in BpsMIP) im Vergleich zu den FKB-Proteinen um zwei Aminosäuren verkürzt. Dadurch befindet sich das Proteinrückgrat von LpnMIP (Gln49) und TcrMIP (Arg49) näher am Zentrum der Bindetasche (definiert als Ile56, welches durch die Pipecolinsäureesterfunktion der Liganden adressiert wird). MD-Simulationen der beiden Apoproteine belegten, dass die geringere Distanz nicht durch Artefakte beim Modellieren der Strukturen bedingt ist. Aufbauend auf dieser Erkenntnis wurde gezeigt, dass der Pyridinylring von Ref_p eine Wasserstoffbrücke zu Gln49 ausbildet. Experimentell wurde dieser Befund durch eine entsprechende chemische Verschiebung der Aminosäure im NMR-Experiment von Dr. Kristian Schweimer bestätigt. Durch Überbrückung des Pipecolinsäurerings (Ligand 6bp) konnte die Wasserstoffbrücke in MD-Simulationen weiter stabilisiert werden. Durch Rechnungen zur Abschätzung der freien Bindungsenthalpien (mittels LIE und MM/GBSA) wurde eine erhöhte Affinität von 6bp im Vergleich zu Ref_p in LpnMIP ermittelt. Im Laufe der Arbeit wurde anhand von pIC50-Werten, welche von Dr. Mathias Weiwad bestimmt wurden, erkannt, dass Liganden mit Pyridinylring oftmals eine bessere Affinität in LpnMIP aufweisen als die entsprechenden Liganden mit TMPR. Durch MD Simulationen wurde nachgewiesen, dass der TMPR in LpnMIP nur schwer an der in den anderen Proteinen bevorzugten Position binden kann. Grund hierfür ist die Mutation einer Aminosäure (zu Pro57) in diesem Bereich von LpnMIP: Diese verfügt über eine wenig flexible Seiten-kette, an welche sich der TMPR auf Grund seiner Rigidität nicht anpassen kann, was die Interaktion zwischen Protein und Ligand stört. Der Pyridinylring von Ref_p ist hiervon nicht betroffen, da er bevorzugt an einer anderen Stelle (Gln49, s. o.) bindet. Der 80er Loop weist in vielen MIP-Proteinen deutlich hydrophobere Aminosäuren auf als in FKB-Proteinen. Von besonderem Interesse ist die Position 90, da hier in BpsMIP und LpnMIP sterisch weniger anspruchsvolle Aminosäuren (Val, Pro) vorliegen als in den bei-den FKB-Proteinen (Ile, Lys). Dieser Unterschied wurde mit kleinen hydrophoben Substituenten am Phenylring der Liganden adressiert. Bereits im Docking zeigten sich die positiven Effekte der para-Substitution durch Halogenatome oder eine Methylgruppe. Die von Dr. Mathias Weiwad und Dr. Mirella Vivoli ermittelten pIC50- bzw. pKi-Werte bestätigten diesen Trend. Zugleich nahm die Affinität zu FKBP12 deutlich ab. Bei der Untersuchung der Referenzliganden sowie deren Chlor- und Bromderivate in MD-Simulationen zeigte sich, dass der Phenylring der Liganden in den MIP-Proteinen bevorzugt in Richtung des 80er Loops orientiert ist; in den FKB-Proteinen liegt er hingegen um etwa 110° gedreht vor und kann somit schlechter mit der Bindetasche interagieren. Besonders ausgeprägt ist dieser Effekt in FKBP12. Basierend auf diesen Ergebnissen wurde der Phenylring durch einen 4-Bromo-1H-imidazol-2-ylsubstituenten ersetzt (Ligand 8ap). Dieser ist in der Lage, in der erwarteten Orientierung im Bereich des 80er Loops von BpsMIP zu binden und gleichzeitig eine stabile Wasserstoffbrücke zu Asp37 auszubilden. Hieraus resultiert für den Liganden eine deutlich höhere Affinität in LIE- und MM/GBSA-Rechnungen; in FKBP12 blieb sie auf Grund der dort instabilen Interaktion unverändert. Die berechneten Energien können unmittelbar für einen relativen Vergleich verschiedener Liganden in einer Bindetasche verwendet werden. Für die Vorhersage von pKi- bzw. pIC50-Werten in den verschiedenen Proteinen ist eine Kalibrierung gegen die gemessenen Affinitäten erforderlich. Dies wurde für BpsMIP durchgeführt, indem eine lineare Korrelation zwischen den pKi- bzw. pIC50-Werten und den mit MM/GBSA ermittelten Energien aufgestellt wurde. Für LIE wurde auf publizierte Werte von Lamb et al. zurückgegriffen. Die berechneten Affinitäten stimmen für die bereits getesteten Inhibitoren gut mit den experimentellen pKi- und pIC50-Werten überein. Anhand der Modelle werden für 8ap Werte vorhergesagt, die besser als die experimentellen Affinitäten bekannter Liganden sind. Idealerweise können auch aus den Scores, die durch Docking erhalten werden, bereits Rückschlüsse auf die Affinitäten der Liganden gezogen werden. Für die untersuchten Proteine war dies, auf Grund des engen Bereichs der experimentell ermittelten pKi- und pIC50-Werte, nicht mit hinreichender Richtigkeit möglich. Um die Scores dennoch für die Beurteilung neuer Liganden verwenden zu können, wurden logistische Regressionsmodelle erstellt. Anhand dieser kann abgeschätzt werden, ob ein Molekül in BpsMIP submikromolare Affinität aufweist. Die Richtigkeit dieser Vorhersagemodelle konnte durch die Berücksichtigung dreier weiterer Deskriptoren (Konfiguration am Stereozentrum der Pipecolinsäure, Molekulargewicht und logD-Wert) deutlich verbessert werden, wobei die AUC der entsprechenden ROC-Kurven Werte bis zu 0.9 erreichte. Diese Modelle können für die Postprozessierung eines Dockings angewendet werden, um die vielversprechendsten Kandidaten zu identifizieren und anschließend in rechnerisch anspruchsvolleren MD-Simulationen genauer zu untersuchen. Mit dieser Arbeit wurde zur Weiterentwicklung der Leitstrukturen Ref_t und Ref_p beigetragen. Viele der getesteten Derivate wiesen deutlich verbesserte Löslichkeit bei gleichbleibender Affinität auf. Ferner wurden erstmalig detailliert die Unterschiede in den Bindetaschen zwischen 32 MIP- und FKB-Proteinen evaluiert. Hiervon wurden fünf in MD-Simulationen als Apoprotein und im Komplex mit verschiedenen Inhibitoren verglichen. Anhand dieser Simulationen wurde nachgewiesen, dass jeweils eine Aminosäure in BpsMIP und LpnMIP im Vergleich zum wichtigsten „off-target“ FKBP12 selektiv durch eine Wasserstoffbrücke adressiert werden kann. Durch LIE- und MM/GBSA-Rechnungen konnte gezeigt werden, dass in diesen hochkonservierten Bindetaschen eine bedeutende Modulation der Affinität zugunsten von BpsMIP möglich ist. / Bacterial and parasitic MIP proteins constitute important virulence factors. Inhibiting these proteins can considerably reduce the survival of the pathogens as well as their penetration into human host cells. The work presented in this thesis focused on the MIP proteins of Burkholderia pseudomallei (the causative agent of melioidosis) and Legionella pneumophila (Legionnaires’ disease). Furthermore, the MIP protein of Trypanosoma cruzi (Chagas disease) was also investigated. The structurally homologous human FKB proteins FKBP12 and FKBP52 were taken into account as relevant off-targets. The aim of this thesis was to improve MIP inhibitors by means of in silico methods with respect to affinity and selectivity (for MIP proteins over FKBP12 and FKBP52) as well as solubility. The starting point for this task were two lead structures with a pipecolic acid scaffold from the work of Dr. Christina Juli and Dr. Florian Seufert. These reference ligands contain a 3,4,5-trimethoxyphenyl ring (TMPR, cf. Ref_t) or a pyridinyl ring (Ref_p). By comparison of 32 MIP and FKB proteins major differences with regard to the amino acid sequence could be identified in two loop regions, the so called 50s and 80s loop (numbering always with respect to FKBP12). It was possible to utilise these differences for the design of molecules with preferential binding to MIP proteins. The 50s loop is truncated by two amino acids in nearly all MIP proteins compared to the FKB proteins, except for BpsMIP. Thus, the protein backbone of LpnMIP (Gln49) and TcrMIP (Arg49) is located closer to the centre of the binding pocket. The centre is defined as Ile56, which is binding to the pipecolic ester function of the ligands. MD simulations of both apoproteins proved that the smaller distance is not caused by artefacts introduced during modelling of the structures. Expanding on this knowledge, it could be shown that the pyridinyl ring of Ref_p forms a hydrogen bond to Gln49. This finding was proven ex-perimentally by a corresponding chemical shift of the amino acid in an NMR experiment conducted by Dr. Kristian Schweimer. The hydrogen bond was stabilised further in MD simulations via bridging of the pipecolic acid ring (ligand 6bp). Calculations by MM/GBSA and LIE, estimating the binding free energies of the ligands, yielded im-proved affinity for 6bp compared to Ref_p in LpnMIP. It was noted in the course of this work, based on pIC50 measurements conducted by Dr. Mathias Weiwad, that ligands containing a pyridinyl ring often exhibit better affinity in LpnMIP than their corresponding counterparts with a TMPR. It could be shown with MD simulations that the TMPR is barely able to bind to LpnMIP at the position preferred in the other proteins. This is caused by mutation of an amino acid (to Pro57) in this region of LpnMIP. Due to its rigidity, the TMPR is not able to adjust to the hardly flexible side chain of proline. Consequently, the interaction between protein and ligand is disrupted. The pyridinyl ring of Ref_p is not affected by this mutation since it binds at another position (Gln49, see above). The 80s loop contains more hydrophobic amino acids in MIP proteins than in FKB proteins. Position 90 is of particular interest, as there are sterically less demanding amino acids in BpsMIP and LpnMIP (Val, Pro) than in both FKB proteins (Ile, Lys). This difference was addressed with small hydrophobic substituents at the ligands’ phenyl ring. The favourable effects of the substitution in para-position by halogen atoms or a methyl group could be observed in initial docking experiments. pIC50 and pKi values measured by Dr. Mathias Weiwad und Dr. Mirella Vivoli confirmed this trend. Furthermore, the affinity for FKBP12 clearly decreased. MD simulations of both reference ligands as well as their derivatives substituted with chlorine or bromine showed that the phenyl ring preferentially adopts a conformation pointing towards the 80s loop in MIP proteins. In contrast, the phenyl ring is rotated by approximately 110° in FKB proteins, leading to decreased interactions with the binding pocket. This effect is especially pronounced in FKBP12. Based on these results, the phenyl ring was substituted by 4-Bromo-1H-imidazol-2-yl (ligand 8ap). A ligand containing this substituent can bind next to the 80s loop of BpsMIP maintaining the previously described orientation and simultaneously form a stable hydrogen bond to Asp37. Hence, a considerably higher binding affinity of this ligand to BpsMIP was predicted via LIE and MM/GBSA calculations. There were no changes in affinity for FKBP12 due to the instable interaction in this protein. The calculated energies can directly be used to rank different ligands in a binding pocket. In order to predict pIC50 and pKi values in different proteins, these energies require calibration versus experimentally measured affinities. Such a calibration was carried out for BpsMIP by linearly correlating pIC50 and pKi values with energies gained from MM/GBSA calculations. For the LIE method, parameters published by Lamb et al. were used. Both computational approaches yielded affinities in good agreement with experimentally measured pIC50 and pKi values of known ligands. The affinities predicted by these models for 8ap are better than the inhibition constants of all currently known inhibitors. Ideally, scores obtained by docking can directly be used to gain insights into the ligands’ affinities. However, sufficient accuracy for the proteins investigated could not be gained, due to the narrow range of the experimental pIC50 and pKi values. Consequently, logistic regression models were created to allow for assessment of the ligands based on their score. These models predict whether a ligand is likely to show submicromolar affinity in BpsMIP. The accuracy of these models was considerably increased by implementing three other descriptors (configuration at the stereo centre of the pipecolic acid, molecular weight and logD value). Thus, AUCs up to 0.9 could be achieved in the corresponding ROC curves. The models can be used for postprocessing a docking calculation in order to identify the most promising ligands and subsequently investigating them with computationally more demanding MD simulations. This work contributed to the improvement of the lead structures Ref_t and Ref_p. Many of the tested derivatives exhibited increased solubility while affinity was maintained. Furthermore, differences in the binding pockets of 32 MIP and FKB proteins were evaluated in detail for the first time. Five of these proteins were compared in MD simulations, both as apoproteins as well as complexed with different inhibitors. It was proven by these simulations that one amino acid in BpsMIP as well as in LpnMIP can selectively be addressed with a hydrogen bond. These interactions cannot be formed in the most prominent off-target FKBP12. LIE and MM/GBSA calculations proved that considerable modulation of the binding affinity towards BpsMIP is possible in these highly conserved binding pockets.

The spectral line-shape of the mid-IR absorption spectrum provides valuable information about the "hole" polaron coherence length in doped and undoped conjugated polymer films. In poly(3-hexylthiophene) (P3HT) films the spectrum generally consists of a narrow, low-energy peak A (700-1000 $cm^{-1}$) followed by a much broader, higher-energy peak B (2500-5000 $cm^{-1}$). Using a theory based on the Holstein Hamiltonian for mobile holes in P3HT, the IR line-shape is successfully reproduced for several recently measured spectra recorded in doped and undoped films, confirming the association of an enhanced peak ratio (A/B) with extended polaron coherence. Emphasis is placed on the origin of components polarized along the intra- and inter-chain directions and their dependence on the spatial distribution of disorder as well as the position of the dopant relative to the $\pi$-stack. The model is further adapted to treat donor-acceptor copolymers where the local HOMO energy varies periodically from donor unit to acceptor unit. The calculated line shape for a diketopyrrolopyrrole-based copolymer agrees well with the recently measured spectrum. / Chemistry

Density functional theory (DFT), a powerful toolbox, can unveil chemical transformations in detail. This dissertation focuses on exploring catalytic puzzles, deciphering experimental results, and occasionally, reevaluating conventional concepts. In the first problem, a combination of DFT and kinetic studies uncovers the hidden role of borane in directed borylation reactions catalyzed by iridium complex. Borane, initially considered a side product, is revealed to be an autocatalyst. Chiral catalysts are pivotal for achieving asymmetric molecular construction. However, when the chirality center in the catalyst changes with each turnover, what impact does this have? In our second investigation, we delved into a thorough mechanistic study of enantiomeric selectivity during ruthenium complex-catalyzed hydroarylation. This study leads to a reevaluation and refinement of our concepts of asymmetric induction, specifically tailored to dynamic chirality. A series of six Ni(II) complexes featuring N-heterocyclic carbene (NHC) ligands demonstrate photocatalytic CO2 reduction to CO. Remarkably, these complexes retain their activity even in the absence of a photosensitizer, exhibiting self-sensitized photocatalytic capabilities. Our investigation involved ultrafast transient absorption spectroscopy (TAS) experiments and computational studies to provide a deeper understanding of these catalytic activities. Throughout my PhD journey at Mississippi State University, I engaged in diverse research areas within the chemistry department. The final chapter presents a series of chemistry problems encountered in the Hand Lab, where the application of DFT offers insightful solutions. These problems emerged from discussions and collaborations among graduate students, reflecting the spirit of teamwork and collective problem-solving in the department: 1. Understanding electronic structure of FAVE polymer (Smith lab); 2. Explaining the unexpected isomerization of RhCl(3-Si,Si,P) complex (Montiel lab); 3. Understanding stable dinitrogen pincer abnormal CCCPt(N2) complex (Hollis lab) and 4. Characterization of Ni tripodal PE (E = Si, Ge) complexes and studies on the hydroboration mechanism (Montiel lab)

Ionic liquids (IL) are salts which are liquid at low temperatures, typically with melting points under 100 °C. In recent years ILs have been treated as novel solvents and used in a wide variety of applications such as analytical and separation processes, electrochemical devices and chemical syntheses. The properties of many ILs have been extensively studied; these studies have primarily focused on the investigation of key physical properties including viscosity, density and solubility. This thesis presents mass spectrometry (MS) and computational data to investigate the intrinsic interactions between a small number of IL ions and also their interactions with contaminants. MS was used to study gas-phase aggregates of three ILs based on the 1-butyl-3- methylimidazolium (C4mim+) cation. The influence of different ion sources was investigated on C4mimCl. Conventional electrospray ionisation (ESI) and nano-ESI techniques were compared with recently developed sonic-spray ionisation (SSI) and plasma assisted desorption ionisation (PADI). SSI was found to be beneficial to the formation of larger aggregates while PADI was significantly less efficient. Gas-phase structures of the singly charged cationic aggregates of C4mimCl were characterised with the aid of collision induced dissociation (CID) and density functional theory (DFT) calculations. Additionally, CID and DFT gave consistent results for the relative stability of the C4mimCl aggregates, showing a good agreement between experiment and theory. Mixed solutions of C4mimCl with a range of metal chloride salts were used to form aggregates incorporating both IL and metal chlorides. LiCl, NaCl, KCl, CsCl, MgCl2 and ZnCl2 were all combined with C4mimCl. Magic number characteristics were observed for a number of pure IL and mixed aggregates. Many of the mixed species were characterised using MS and DFT calculations. In particular, the relative stabilities were determined and the structures of the aggregates were calculated. It was found that the metal ions would normally act as a core for the aggregates with the stability determined by the metal-chlorine binding strength and the steric hindrance of the aggregates. It was necessary to exploit pseudopotentials as opposed to all-electron basis sets for the larger aggregates and aggregates containing heavy atoms. While water is a very effective contaminant for ILs it was not possible to observe gas-phase IL aggregates incorporating this despite using multiple methods. Additionally the presence of protonated aggregates was likewise not observed throughout the range of experiments. Possible structures where these features would be incorporated were studied with DFT to obtain some insight into their lack of formation.

Aggregation of amyloid β (Aβ) protein has been linked to the development of Alzheimer's Disease (AD). The genesis of Aβ involves the cleavage Amyloid Precursor Protein (APP) by β-secretase, producing the 99-residue C99 peptide, and the subsequent cleavage of C99 by γ-secretase to produce Aβ. A detailed understanding of the γ-cleavage process is essential to our undertsanding of the pathological mechanisms linking the aggregation of Aβ to the development of AD. This work seeks to provide insight into critical aspects of the structure and dynamics of C99, and the particular roles played by (1) C99 amino acid sequence and (2) the lipid composition of the membrane environment. Many studies have focused on the importance of the C99 sequence, including known studies of Familial AD (FAD) mutants as well as engineered mutations. Specific mutations have been found to affect the processing of C99, which has been linked to changes in the structure of C99 and the formation of C99 homodimers. Similarly, changes in the membrane environment, through variation in lipid composition and the presence of cholesterol, have been found to affect C99 structure and positioning within the membrane as well as C99 dimerization. The results of this work extend our understanding of the APP-C99 system and its interaction with the environment. Using a multiscale simulation approach, we find key structural effects of engineered mutations that suggest possible mechanistic insight into the γ-cleavage process. Using C99 congener peptides, we examine the effect of local membrane environment on the dimerization of C99, focusing on the roles of both the transmembrane (TM) region as well as the juxtamembrane (JM) domain. Further studies characterize the role of a FAD mutation, and demonstrate the effect of the mutation on the dimerization of C99 in agreement with experimental findings. Overall, this work leads to critical insight into the role of sequence and membrane on the structure of C99 in a membrane environment, and provides support for the conjecture that the structure of C99 monomer and homodimer are critical to our understanding of the processing of C99, a critical step in the genesis of Aβ peptide and the etiology of Alzheimer's Disease.

Computational simulations of chemical systems play an ever-increasing role in many areas of biochemical research from rational drug design to probing fundamental physiological processes. Depending on the method, a vast array of properties are able to be predicted. Here we report the design and implementation of two methods for investigating diverse problems in protein biochemistry. In order to better understand protein–metal interactions—most importantly for the difficult to model transition metal ions— empirical force field parameters were developed for Pt(II), cisplatin, and other Pt(II) coordination compounds. Two force field frameworks were used: a modified version of the fixed- charge OPLS-AA and the polarizable POSSIM force field. A seven-site model was used for the Pt(II) ion. The produced parameters are compatible with the OPLS-AA and POSSIM force fields and can be used in protein–metal binding simulations in which—contrary to the common treatment of metal ions in such simulations—the position or even coordination of the ion does not have to be constrained using preexisting knowledge. It has been demonstrated that the produced models are capable of reproducing key properties of relevant Pt(II) complexes but that the POSSIM formalism yields more accurate values for energies of formation than the OPLS-AA model. This Pt(II) model was employed—along with previously developed Cu(I) parameters—to investigate the binding of platinum to the protein Atox1, a human copper chaperone implicated in the resistance mechanism of cisplatin and other platinum antitumor compounds. In collaboration with the Dmitriev and Bernholc groups, we used our models to inform and refine spectroscopic experiments as well as to serve as starting points for high-performance quantum calculations. It was shown that under physiological redox conditions, copper(I) and cisplatin can form large polymers with glutathione. These polymers were capable of transferring copper(I) to apo-Atox1 or to platinum(II) to copper-loaded Atox1. Analysis of the simultaneous binding of copper(I) and platinum(II) to Atox1 was found to occur through the formation of copper–sulfur–platinum bridges, where copper is coordinated by three sulfur atoms and platinum by four sulfur atoms. With the goal of using a simple model to be able to quickly estimate the acid disassociation constants of proteins, PKA17 has been developed and tested. PKA17 is a coarse-grain grid-based method and software tool for accurately and rapidly calculating protein pKa values given an input PDB structure file. During development, parameter fitting was carried out using a compilation of 442 Asp, Glu, His, and Lys residues that had both high-resolution PDB structures and published experimental pKa values available. Applying our PKA17 model, the calculated average unsigned error and RMSD for the residue set were found to be 0.628 and 0.831 pH units, respectively. As a benchmark for comparison, the same residue set was evaluated with the PROPKA software package which resulted in an average unsigned error of 0.761 pH units and an RMSD of 1.063 pH units. Finally, a web interface for the PKA17 software was developed and deployed (http://users.wpi.edu/~jpcvitkovic/pka_calc.html) to make PKA17 available to the wider scientific community.

This thesis explores the use of computational chemistry to aid in the design of metal-organic frameworks (MOFs) and other materials. A focus is placed on finding exceptional materials to be used for removing CO2 from fossil fuel burning power plants, with other avenues like vehicular methane storage and landfill gas separation being explored as well. These applications are under the umbrella of carbon capture and storage (CCS) which aims to reduce carbon emissions through selective sequestration. We utilize high-throughput screenings, as well as machine learning assisted discovery, to identify ideal candidate materials using a holistic approach instead of relying on conventional gas adsorption properties. The development of ideal materials for CCS requires all aspects of a material to be considered, which can be time-consuming. A large portion of this work has been with high-throughput, or machine learning assisted discovery of ideal candidates for CCS applications. The chapters of this thesis are connected by the goal of finding ideal materials for CCS. They are primarily arranged in increasing complexity of how this research can be done, from using high-throughput screenings with more simple metrics, up to multi-scale machine learning optimization of pressure swing adsorption systems. The work is not presented chronologically, but in a way to tell the best story. Work was done by first applying high-throughput computational screening on a set of experimentally realized MOFs for vehicular methane storage, post-combustion carbon capture, and landfill gas separation. Whenever possible, physically motivated figures of merits were used to give a better ranking and consideration of the materials. From this work, we were able to determine what the realistic limits might be for current MOFs. The work was continued by looking at carbon-based materials (primarily carbon nanoscrolls) for post-combustion carbon capture and vehicular methane storage. The carbon-based materials were found to outperform MOFs; however, further studies are needed to verify the results. Next, we looked at ways to improve the high-throughput screening methodology. One problem area was in the charge calculation, which could lead to unrealistic gas adsorption results. Using the split-charge equilibration method, we developed a robust way to calculate the partial atomic charges that were more accurate than its quick calculation counterparts. This led to gas adsorption properties which more closely mimicked the results determined from time-consuming quantum mechanically derived charges. Simplistic process optimization was then applied to nearly ~3500 experimental structures. To the best of our knowledge, this is the first time that any process optimization has been applied to more than 10s of materials for a study. The process optimization was done by evaluating the desorption at various pressures and choosing the value which gave the lowest energetic cost. It was found that a material synthesized by our collaborators, IISERP-MOF2, was the single best experimentally realized material for post-combustion carbon capture. What made this an interesting result is that by conventional metrics IISERP-MOF2 does not appear to be outstanding. Next, functionalized versions of MOFs were tested in a high-throughput manner, and some of those structures were found to outperform IISERP-MOF2. Although high-throughput computational screenings can be used to determine high-performance materials, it would be impossible to test all functionalized versions of some MOFs, let alone all MOFs. Functionalized MOFs are noteworthy because MOFs are highly tuneable through functionalization and can be made into ideal materials for a given application. We developed a genetic algorithm which, given a base structure and a target parameter, would be able to find the ideal functionalization to optimize the parameter while testing only a small fraction of all structures. In some cases, the CO2 adsorption was found to more than quadruple when functionalized. A better understanding of how materials perform in a PSA system was achieved by performing multi-scale optimizations. Experimentally realized MOFs were tested using atomistic simulations to derive gas adsorption properties. After passing through a few sensible filters, they were then screened using macro-scale pressure swing adsorption simulators, which model how gas separation may occur at a power plant. Using another genetic algorithm, the conditions that the pressure swing adsorption system runs at was optimized for over 200 materials. To the best of our knowledge, this is the highest amount of materials that have had been optimized for process conditions. IISERP-MOF2 was found to perform the best based on many relevant metrics, such as the energetic cost and how much CO2 was captured. It was also found that conventional metrics were unable to be used to predict a material’s pressure swing adsorption performance.

Organic and organometallic electronic materials continue to attract considerable attention among researchers due to their cost effectiveness, high flexibility, low temperature processing conditions and the continuous emergence of new semiconducting materials with tailored electronic properties. In addition, organic semiconductors can be used in a variety of important technological devices such as solar cells, field-effect transistors (FETs), flash memory, radio frequency identification (RFID) tags, light emitting diodes (LEDs), etc. However, organic materials have thus far not achieved the reliability and carrier mobility obtainable with inorganic silicon-based devices. Hence, there is a need for finding alternative electronic materials other than organic semiconductors to overcome the problems of inferior stability and performance. In this dissertation, I research the development of new transition metal based electronic materials which due to the presence of metal-metal, metal-?, and ?-? interactions may give rise to superior electronic and chemical properties versus their organic counterparts. Specifically, I performed computational modeling studies on platinum based charge transfer complexes and d10 cyclo-[M(?-L)]3 trimers (M = Ag, Au and L = monoanionic bidentate bridging (C/N~C/N) ligand). The research done is aimed to guide experimental chemists to make rational choices of metals, ligands, substituents in synthesizing novel organometallic electronic materials. Furthermore, the calculations presented here propose novel ways to tune the geometric, electronic, spectroscopic, and conduction properties in semiconducting materials. In addition to novel material development, electronic device performance can be improved by making a judicious choice of device components. I have studied the interfaces of a p-type metal-organic semiconductor viz cyclo-[Au(µ-Pz)]3 trimer with metal electrodes at atomic and surface levels. This work was aimed to guide the device engineers to choose the appropriate metal electrodes considering the chemical interactions at the interface. Additionally, the calculations performed on the interfaces provided valuable insight into binding energies, charge redistribution, change in the energy levels, dipole formation, etc., which are important parameters to consider while fabricating an electronic device. The research described in this dissertation highlights the application of unique computational modeling methods at different levels of theory to guide the experimental chemists and device engineers toward a rational design of transition metal based electronic devices with low cost and high performance.