Mass spectrometry with electrospray ionization is an excellent method for structural analysis of coordination compounds with outstanding sensitivity and selectivity. However, it fails to detect some low-polar rhenium complexes. This master thesis describes derivatization method of non-ionizable rhenium complexes with 1,2-dihydroxybenzene and 2,3- dihydroxytoluenene. Fragmentation mechanisms and structure of prepared complexes was studied using high resolution mass spectrometry and collision-induced dissociation (CID). Furthermore, density functional theory (DFT) computational method was used for prediction of bond cleavage based on bond lengthening.

<div>Deep neural networks (DNNs) have gained tremendous attention over the recent years due to their outstanding performance in solving many problems in different fields of science and technology. Currently, this field is of interest to many researchers and growing rapidly. The ability of DNNs to learn new concepts with minimal instructions facilitates applying current DNN-based methods to new problems. Here in this dissertation, three methods based on DNNs are discussed, tackling different problems in the field of computer-aided drug design.</div><div><br></div><div>The first method described addresses the problem of prediction of hydration properties from 3D structures of proteins without requiring molecular dynamics simulations. Water plays a major role in protein-ligand interactions and identifying (de)solvation contributions of water molecules can assist drug design. Two different model architectures are presented for the prediction the hydration information of proteins. The performance of the methods are compared with other conventional methods and experimental data. In addition, their applications in ligand optimization and pose prediction is shown.</div><div><br></div><div>The design of de novo molecules has always been of interest in the field of drug discovery. The second method describes a generative model that learns to derive features from protein sequences to design de novo compounds. We show how the model can be used to generate molecules similar to the known for the targets the model have not seen before and compare with benchmark generative models.</div><div><br></div><div>Finally, it is demonstrated how DNNs can learn to predict secondary structure propensity values derived from NMR ensembles. Secondary structure propensities are important in identifying flexible regions in proteins. Protein flexibility has a major role in drug-protein binding, and identifying such regions can assist in development of methods for ligand binding prediction. The prediction performance of the method is shown for several proteins with two or more known secondary structure conformations.</div>

<div>Conventional soybean oil and high-oleic soybean oil offer opportunities as bio-solvents for sweetening sour natural gas, adding value to the soybean oil industry and the natural gas industry. The rise of fracking in the United States and changing economics in the energy industry have increased use of natural gas, which is often rendered sour by high concentrations of hydrogen sulfide (H2S), a toxic and corrosive impurity. The present work evaluates the viability of both conventional and high-oleic soybean oil to act as bio-solvents for removing gaseous H2S. Predictive in silico methods, experimental validation, and economic feasibility analysis are included to draw conclusions regarding the overall capability and feasibility of using soybean oils as bio-solvents for gas sweetening.</div><div><br></div><div>In silico predictive methods for sweetening were implemented to assess the relationship between fatty acid composition in the soybean oils and the ability to effectively partition H2S from methane or nitrogen gases. The Conductor-like Screening Model for Real Solvents (COSMO-RS) was used to predict the partition coefficient (K) of H2S in a bi-phasic liquid-vapor system made up of fatty acids in the liquid phase and methane or nitrogen gas in the vapor phase. The fatty acid mass fractions represented those found in soybean or high-oleic soybean oil. Methane represented gas and nitrogen was considered in order to compare to experimental conditions. This proof of concept work predicted K values for H2S below 0.0005 at temperatures from 10 to 100 °C at atmospheric pressure; K values near zero indicate near-complete removal of H2S from the gas phase.</div><div><br></div><div>Experimental validation included equilibrium extraction experiments as well as data collection for isotherm model development. Experimental equilibrium studies were carried out at residence times ranging from 0 – 60 minutes with mixing at ambient conditions. Experiments resulted in K values below 0.1 for H2S in soybean oil and high-oleic soybean oil at 25 °C with residence times less than 15 minutes and a 2:1 gas to oil ratio. More than 90% of the H2S was removed from the gas phase within 15 minutes. Isotherm models demonstrated the saturation limits of the soybean oils and compared them to saturation limits in water and heptane. </div><div><br></div><div>Economic feasibility experiments used graphical and algebraic methods to determine the number of equilibrium stages needed to remove 99.9% of H2S from feed gas with H2S concentrations ranging from 40 – 400 ppm. A gas flow rate equivalent to industrial levels was used to design an extraction column. Capital costs and operating costs were estimated, along with the revenues to be gained from selling methane and selling recovered elemental sulfur as a secondary product. Solvent regeneration would need to exceed 98% in order to keep the cost of treating a unit of natural gas equal to or less than existing industrial methods. Suggestions for cutting costs and improving process viability are made.</div><div><br></div>

The work described herein is related to gas-phase ion-molecule reactions studied by using mass spectrometry. Chapter 2 describes density functional theory, a method used in chapters 4 and 5 to propose reaction mechanisms for reactions previously observed by others by using mass spectrometry. Chapter 3 describes a study that demonstrates that the fragmentation of saturated hydrocarbons occurs due to proton-transfer reactions that occur between these species and protonated molecules generated from molecules present in air such as nitrogen and water. Saturated hydrocarbons are studied in a wide variety of fields, and better methods to analyze complex mixtures of these compounds would facilitate their analysis. Chapter 4 discusses mechanisms of reactions for previously studied ion-molecule reactions of pyridynes studied by others by using mass spectrometry. Reactions of pyridynes are important to study arynes have been previously used in organic synthesis, and pyridine moieties are particularly common in biological compounds. Chapter 5 discusses density functional theory calculations used to determine why some organic polyradical undergo hydride abstractions from cyclohexane while others do not. The study discusses reactions taking place between both singlet and triplets states of the 2,5-didehydropyridinium cation and cyclohexane as a model, which are compared to reactions of the 2-pyridyl cation and 2-dehydropyridinium cation with cyclohexane. These studies may help improve our understanding of the reactivity-controlling factors of organic polyradicals, which may help improve toxic drug candidates like cytostatic enediynes.

<p>Mass spectrometry (MS) is a versatile analytical tool that is especially useful for identification of unknown compounds in mixtures when coupled with chromatography. In MS experiments, the analytes are ionized, separated based on their mass-to-charge (<i>m/z</i>) ratios, and detected. The molecular weight of the analyte can often be derived from the mass spectrum if stable molecular ions (M^•+) or stable protonated/deprotonated analyte molecules ([M+H]⁺ or [M-H]^–) are generated. Further, MS can also be used to obtain structural information for the ionized analytes via their fragmentation reactions. Tandem mass spectrometry (MSⁿ) experiments are powerful for the characterization of unknown compounds in mixtures without the need for coupling them with chromatography. In MSⁿ experiments, the analytes are ionized, the ions of interest are isolated and subjected to reactions, such as collision-activated dissociation (CAD) or ion-molecule reactions with neutral reagent molecules. The fragmentation pattern or the diagnostic ion-molecule reaction product ions can be utilized to elucidate the structures of the analytes. The fragment ions or diagnostic product ions can further be subjected to CAD to obtain more structural information. Besides analytical purposes, MSⁿ also provides a powerful tool for exploring the reactivities of reaction intermediates that are elusive, such as phenylcarbyne anions and phenylcarbene anions.</p> <p>The research described in this dissertation mainly focuses on the development of MSⁿ methods based on diagnostic gas-phase ion-molecule reactions followed by CAD for (1) the characterization of differently substituted ureas and (2) the differentiation of sulfonate esters from their isomeric analogs, such as sulfite esters and sulfones. HPLC was coupled with the MSⁿ methods discussed above to demonstrate its usefulness in the identification of compounds in mixtures. Additionally, a gas-phase reactivity study on phenylcarbyne anions is discussed in this dissertation. The phenylcarbyne anions were generated by CAD of two nitrogen molecules from negatively charged phenyl tetrazole precursors. Their reactivities towards various reagents were explored and rationalized with the help of quantum chemical calculations.</p>

La caractérisation complète d’intermédiaires réactionnels intervenants dans des procédés de catalyse homogène est une tâche ardue en raison de leur réactivité et de leur faible concentration. Ceci est particulièrement vrai pour les espèces radicalaires telles que les complexes organométalliques réduits, qui sont des intermédiaires en photocatalyse ou lorsque ces complexes possèdent des ligands non-innocents. Par conséquent, leur structure électronique est encore mal comprise, sachant que l'électron ajouté peut être situé sur différents sites de la molécule.Dans ce contexte, nous avons développé une méthode d'analyse pour étudier en phase gazeuse des complexes organométalliques radicalaires. Des complexes organométalliques multichargés du zinc et du ruthénium avec des ligands bidentes de type bipyridine ou tridente de type bis(imino)pyridine ont d’abord été obtenus et isolés en phase gazeuse. Ils sont ensuite réduits avec les méthodes d’activation par un électron spécifiques à la spectrométrie de masse, la dissociation par capture ou transfert d’électron (ECD/ETD), permettant de former des espèces métalliques radicalaires monochargées. Celles-ci sont enfin isolés et leur spectre infrarouge est obtenu à l’aide de la spectroscopie d’action basée sur la dissociation induite par l’absorption de plusieurs photons dans l’infrarouge (IRMPD). Les méthodes DFT fournissent un complément pour modéliser la structure électronique et le spectre IR de ces espèces.Les challenges à relever pour développer ce nouvel outil d'analyse étaient de deux ordres. Tout d'abord, nous devions être en mesure d'obtenir les complexes souhaités en phase gazeuse. Ceci nous a conduit à examiner de multiples paramètres, tels que la nature des ligands ou l’énergie interne déposée lors de l’étape de réduction. Le deuxième défi portait sur l'utilisation des méthodes de modélisation. Nous avons montré l’absence de fiabilité des méthodes standards de modélisation pour décrire à la fois la structure électronique et le spectre infrarouge des complexes réduits. Les données expérimentales obtenues durant ce travail ont donc été utilisées comme références pour identifier les fonctionnelles DFT les plus appropriées pour l’étude de ces complexes radicalaires. / The complete characterization of reaction intermediates in homogeneous catalytic processes is often a difficult task owing to their reactivity and low concentration. This is particularly true for radical species such as reduced organometallic complexes, which are intermediates in photocatalysis, or when these complexes included non-innocent ligands. Consequently, their electronic structure in the ground state is still poorly understood, knowing that the added electron can be located on different sites of the molecule.In this contect, we developed an analytical method to study radical organometallic complexes in the gas phase. We started with formation of suitable multi-charged zinc organometallic complexes in the gas phase from mixture of zinc metal cation and bipyridine-type bidentate or bis(imino)pyridine tridentate ligands. Multicharged ruthenium complexes with similar ligands have also been studied. Under ideal circumstances these complexes were isolated and reduced in the gas phase to form monocationic metal species. Electron activated methods such as electron capture dissociation (ECD) and electron transferred dissociation (ETD) techniques, available in FT-ICR mass spectrometers, have been used to that end. The resulting Zn and Ru radical cation complexes are then isolated in the gas phase and probed via infrared multi photon dissociation (IRMPD) action spectroscopy. In support, DFT theoretical calculations were performed to model their electronic structure and IR spectra.Two main issues were faced during the development of this new analytical tool. First, we had to be able to obtain the desired complexes in the gas phase. This has lead to monitor various parameters, such as the nature of the ligands or the internal energy provided by the reduction step. The second challenge dealt with the use of modeling methods. We have shown that standard modelling tools lack the accuracy to predict both electronic structure and spectral signatures of reduced complexes. The experimental data gathered in this work have therefore been used as benchmarks for the identification of DFT functionals that are most appropriate for the study of these radical complexes.

A bicyclo-[2.2.2]-octa-2,5-diene (BOD) is a molecular photoswitch which makes up a so-called molecular solar thermal energy storage system. A molecular photoswitch has the ability to capture, store and release solar energy as heat. These processes can be enhanced by functional groups introduction. In this thesis, the effect of functional group introductions on the BODs' solar energy storage capacity and the thermal activation energy required for energy release was investigated. Various functional groups were introduced onto the BOD, and the corresponding storage and thermal back conversion energies were computed. Correlations were identified, and further tested using a practical BOD and its related structures. Conclusively, it was revealed that a storage energy might relate to (i) an electron withdrawing functional group strength, and (ii) an electron rich atom placed next to an electron withdrawing group. A dimethyl introduced bridge was observed to reduce storage energy and seemed to have a positive effect on the thermal back conversion barrier energy. The practical BOD λmax calculation was also computed, however, the result was not so promising as expected. Very little could be said about the thermal back conversion barrier energy due to long computational time and unreliable data. / En bicyklisk-[2.2.2]-okta-2,5-dien (BOD) är en molekylär fotoväxlare som ingår i ett så-kallat molekylär sol-termisk energilagrings-system. En molekylär fotoväxlare kan fånga, lagra och släppa tillbaka solenergin i form av värme. Dessa processer kan förstärkas av funktionella gruppers introduktion. I den här kandidatuppsatsen utforskades effekten av introduktion av funktionella grupper på BODs solenergilagrings-kapacitet och den termiska aktiveringsenergin som behövs för energiutlösning.  Olika funktionella grupper introducerades på BODn, och korresponderande lagringsenergier och termiska tillbakaomvandlingsenergier beräknades. Korrelationer identifierades och testades extensivt mot en praktisk BODs och dess relaterade strukturer. Sammanfattningsvis identifierades lagringsenergins möjliga relationer till (i) en elektron-accepterande funktionell grupps stryka, och (ii) en elektron-rik atom placerade nära en elektrondragande grupp. En dimetyl introducerad bro verkade reducera lagringsenergin och positivt påverka den termiska tillbakaomvandlingsenergin. Beräkning av den praktiska BODns λmax gjordes också, men resultatet var inte det förväntade. Mycket begränsade slutsatser kunde dras om den termiska tillbakaomvandlingsenergin på grund av lång beräkningstid och opålitliga data.

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Molecular dynamics (MD) is a powerful tool that can be applied to protein folding and protein structure. MD allows for the calculation of movement, and final position, of atoms in a biomolecule. These movements can be used to investigate the pathways that allow proteins to fold into energetically favorable structures. While MD is very useful, it still has its limitations. Most notable, computing power and time are of constant concern. Protein structure is inherently important due to the direct link between the structure of a protein and its function. One of the four levels of protein structure, the secondary structure, is the first level to accommodate for the three-dimensional shape of a protein. The main driving force behind secondary structure is hydrogen bonding, which occurs between the carboxyl oxygen and the amine hydrogen of the backbone of a peptide. Determining a greater link between hydrogen bond patterns and types of secondary structure can provide more insight on how proteins fold. Because molecular dynamics allows for an atomic level view of the dynamics behind protein folding/unfolding, it becomes very useful in observing the effects of particular hydrogen bond patterns on the folding pathway and final structure formed of a protein. Using molecular dynamic simulations, a series of experiments in an attempt to alter structure, hydrogen bonding, and folding patterns, can be performed. This information can be used to better understand the driving force of secondary structure, and use the knowledge gained to manipulate these simulations to force folding events, and with that, desired secondary structure features.

<p>Bacterial endospores have been a topic of research interest over the last several decades given their high resistance to ultraviolet (UV) damage. Unlike vegetative bacterial cells, which form cyclobutane pyrimidine dimers (CPD) and pyrimidine 6-4 pyrimidone photoproducts (6-4PPs) as the major product upon UV irradiation, endospore bacteria form a spore photoproduct (5-(<em>R</em>-thyminyl)-5,6-dihydrothymine or SP) as the major product. Vegetative bacteria cells are subject to regular cell activities and processes such as division and deoxyribonucleic acid (DNA) replication, which are prone to damage from UV exposure. However, in endospores, which have a largely anhydrous inner environment, the DNA remains dormant when bound to spore-specific small acid-soluble proteins (SASP) and dipicolinic acid, making spores highly resistant to radiation, heat, desiccation, and chemical harm. During spore germination, SP lesions in DNA are repaired by a distinctive repair enzyme, spore photoproduct lyase (SPL). In this thesis, molecular dynamics (MD) simulations were carried out to (i) examine how the formation of the SP lesion in DNA affects the global and local structural properties of duplex DNA and (ii) study how this lesion is recognized and repaired in endospore. The first part of this work was focused on designing and developing a structurally and dynamically stable model for dinucleotide SP molecule (TpT), which was subsequently used as an SP patch incorporated into duplex DNA. Computationally, this requires modifications of the bond and nonbonded force field parameters. The stability of the patch and developed parameters was tested via solution-phase MD simulations for the SP lesion incorporated within the B-DNA dodecamer duplex (PDB 463B). The second part involved applying the new SP patch to simulate the crystallographic structure of the DNA oligomer containing SP lesions. Solution-phase MD simulations were performed for the SP-containing DNA oligomers (modeled based on PDB 4M94) and compared to the simulations of the native structure (PDB 4M95). Our analysis of the MD trajectories revealed a range of SP-induced structural and dynamical changes, including the weakened hydrogen bonds at the SP sites, increased DNA bending, and distinct conformational stability and distribution. In the third part of this thesis project, we carried out MD simulations of SP-containing DNA bound with SASPs to examine how the DNA interacts differently with SASP in the presence and absence of the SP lesion. The simulation results suggested decreased electrostatic and hydrogen bonding interactions between SASP and the damaged DNA at the SP site compared to the undamaged DNA-protein complex. In addition, decreased helicity percentage was observed in the SASPs that directly interact with the SP lesion. The last part of this this thesis work focused on the SP-dimer flipping mechanism, as the lesion is likely flipped out to its extrahelical state to be recognized and repaired by SPL. Using steered molecular dynamic (SMD) simulations and a pseudo-dihedral angle reaction coordinate, we obtained possible SP flipping pathways both in the presence and absence of SASP. Collectively, these simulation results lend new perspectives toward understanding the unique behavior of the SP lesion within the DNA duplex and the nucleoprotein complex. They also provide new insights into how the SP lesion is efficiently recognized and repaired during spore germination.</p>