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This study focused on the preparation and characterization of new indigo diimine (Nindigo) derivatives as a new atropisomeric scaffold. Trans- and cis- indigo diimines were studied and structure-property relationships were investigated regarding N-C atropisomerism using variable temperature 1H NMR studies and density functional theory calculations. Neutral trans- and protonated cis-Nindigos were prepared featuring a variety of mono ortho-substituted aryl imine groups with varying levels of steric bulk. The neutral trans-Nindigo derivatives generally have smaller N-C rotational energy barriers than their protonated cis-congeners. This finding is consistent with the latter having closer proximity of the N-aryl groups to each other, leading to steric repulsions between the two groups. The N-C rotational energy barriers are substituent dependent; the N-C rotational energy barriers of mono ortho substituted trans-Nindigos were in the range of 6.0 – 16.4 kcal/mol and can be classified as predominantly “Class 1’ atropisomers as defined by LaPlante, while the mono ortho substituted protonated cis-Nindigo analogs have N-C rotational barriers between 12.3 – 25.5 kcal/mol and are classified as “Class 1” and “Class 2” atropisomers. The introduction of additional substituents onto the other ortho position of the aryl imine subunit has significant consequences for the N-C rotational energy barriers of both the neutral trans- and protonated cis-Nindigos making them stable, or close to being, ‘Class 3’ atropisomers, having N-C rotational energy barriers between 31.5 – 276.9 kcal/mol and 29.3 – 32.6 kcal/mol respectively. Recognizing that the protonation state induced trans- to cis-isomerization process could have significant consequences regarding the potential applicability of these atropisomeric Nindigo derivatives, cis-Nindigo derivatives were synthesized that contained a tether (oxalyl or palladium (II) acetylacetonate) between the two indole type nitrogens of the Nindigo, which prevent the central -C=C- from isomerizing. The N-C rotational barriers of the tethered cis-Nindigos also displayed substituent dependent N-C rotational energy barriers. The protonation state of the N, N’-oxalyl bridged cis-Nindigos has a significant impact (higher in energy by a minimum of 5.1 kcal/mol) on the N-C rotational barriers; the neutral N, N’-oxalyl bridged cis-Nindigos have N-C rotational energy barriers ranging between 11.8 – 14.9 kcal/mol, classifying them as “Class 1” atropisomers, while their protonated congeners have N-C rotational energy barriers between 16.9 – 19.8 kcal/mol, which classifies them as “Class 1” atropisomers but are on the cusp of being “Class 2” atropisomers. The size of the tether influences the N-C rotational energy barriers of cis-Nindigos; the one-atom bridged palladium (II) acetylacetonate complexes have generally lower N-C rotational energy barriers than their protonated N, N’-oxalyl bridged cis-Nindigo congeners. The palladium acetylacetonate tethered cis-Nindigo complexes displayed substituent N-C rotational energy barrier dependence and the mono ortho substituted analogs have N-C rotational energy barriers between 12.4 – 20.2 kcal/mol and are predominantly “Class 1” atropisomers, while the bulkier analogs are “Class 2” atropisomers. The palladium (II) acetylacetonate cis-Nindigo complexes that have aryl imine groups with a 2,6-disubstitution pattern have N-C rotational energy barriers greater than 19.7 and 20.2 kcal/mol and are presumed to be stable “Class 3” atropisomers like their unbridged neutral trans- and protonated cis-Nindigo counterparts. / Graduate / 2023-09-12

<p dir="ltr">Plant and algae-based biofuels offer a compelling green energy solution, but the utility of biological photosynthesis is limited by inefficiency in energy production. Without the connection between the protein structure and optical spectra, it is challenging to modify optical properties for improving energy production. Chlorophyll proteins (CPs) are the primary work-horses of biological photosynthesis that absorb and transfer solar energy to chemically active reaction centers and control the chemical energy storage process. While the CP structures are well-known, predicting their optical and electronic properties remains a serious challenge. There are computational complications for treating large, electronically coupled molecular pigments embedded in a dynamically structured protein environment. In this work, we aim to address some prominent issues with structure-based optical spectra predictions and the limitations in applying the Frenkel exciton model.</p>

he interactions of the chemical warfare agent sulfur mustard with amorphous silica were investigated using electronic structure calculations. In this thesis, the binding energies of sulfur mustard and mimic species used in the laboratory were calculated using density functional theory and fully ab initio calculations. The wB97XD and B97D functionals, which include functions to account for long-range dispersion interactions, were compared to experimental trends. The hydroxylated amorphous silica surface was approximated using a gas-phase silanol molecule and clusters containing a single hydroxyl moiety. Recent temperature programmed desorption experiments performed in UHV concluded that sulfur mustard and its less toxic mimics undergo molecular adsorption to amorphous silica. Hydrogen bonding can occur between surface silanol groups and either the sulfur or chlorine atom of the adsorbates, and the calculations indicate that the binding energies for the two hydrogen bond acceptors are similar. The adsorption of sulfur mustard and its mimics on silica also exhibits the presence of significant van der Waals interactions between alkyl of the adsorbates and the surface. These interactions, in combination with the formation of a hydrogen bond between a surface silanol group and the Cl or S atoms of the adsorbates, provide remarkably large binding energies. / Master of Science

Yes / The creation of multi-component crystals between chiral and achiral components has gained increased interest in recent years. In many cases the overall crystal structure is similar with the creation of a pseudo-inversion centre in the enantiopure case. This allows for the formation of solid solutions between the two extremes, which may have applications within chiral resolution. Utilising a combination of database mining, computational prediction and experimental screening, the frequency of formation for such materials has been investigated showing that for co-crystals this occurs more frequently than for salts, though there is a limited number of samples to draw structural conclusions. Computational modelling indicates the prediction of such systems can be challenging due to the similarities in energy of many crystal structures, so development of tools to design such systems is required to fully utilise these concepts. / The Deanship of Scientific Research at Princess Nourah bint Abdulrahman University through the Fast-track Research Funding Program.

This workd presents studies of enzyme dynamics and enzyme-inhibitor reactions in several proteins using molecular mechanics (MM), quantum mechanics (QM), and hybrid molecular mechanics/quantum mechanics (QM/MM) methods. QM model calculations were employed to investigate inhibition reactions and compare our mechanistic findings with experimental results. The QM model approach is also applied to RNA targeting covalent ligands to discern the experimentally observed selectivity for certain nucleobases. This work includes a study of lysine as a potential drug target, using QM/MM MD simulations to explore the reaction of the kinase PI3Kα with wortmannin. Chapter 7 of this thesis examines the inhibition pathway of rhodesain by vinyl sulfone K11777, with a focus on the effect of Umbrella Sampling settings, such as QM size and selection. In addition, an analysis of the enzyme environment is performed to elucidate the influence on the calculated reaction path. Furthermore, we evaluated the reliability of the AMBER ff14SB and ff19SB force fields in reproducing the crystal structure conformations of a tryparedoxin mutation. Subsequently, the tested force fields were applied to explain the loss of activity when mutating three amino acids forming the hydrophobic lid of tryparedoxin. The investigations presented in this thesis have allowed the assessment of the capabilities and limitations of computational tools in understanding enzyme functionality and facilitating drug discovery. Additionally, they provide deep insights into the intricate reaction mechanisms of various inhibitors and the functionality of the oxidoreductase tryparedoxin. / In dieser Arbeit werden Untersuchungen zur Enzymdynamik und zu Enzym-Inhibitor-Reaktionen von verschiedenen Proteinen mit Methoden der Molekularmechanik (MM), der Quantenmechanik (QM) und des hybriden QM/MM Ansatz vorgestellt. QM-Modellrechnungen wurden eingesetzt, um Inhibitionsreaktionen zu untersuchen und die daraus gewonnenen mechanistischen Erkenntnisse mit experimentellen Ergebnissen zu vergleichen. Der QM-Modellansatz wurde auch auf einen kovalenten RNA-Liganden angewandt, um die experimentell beobachtete Selektivität für bestimmte Nukleobasen zu untersuchen. Diese Arbeit umfasst eine Studie über Lysin als potenzielles Zielmolekül, wobei QM/MM-MD-Simulationen verwendet wurden, um die Reaktion der Kinase PI3Kα mit Wortmannin zu untersuchen. In Kapitel 7 dieser Arbeit wurde die Inhibition von Rhodesain durch das Vinylsulfon K11777 untersucht, wobei der Schwerpunkt auf den Auswirkungen der Umbrella Sampling-Einstellungen, wie QM-Größe und Auswahl, lag. Darüber hinaus wurde eine Analyse der Enzymumgebung durchgeführt, um den Einfluss auf den berechneten Reaktionsweg zu klären. Des Weiteren wurde die Zuverlässigkeit der AMBER-Kraftfelder ff14SB und ff19SB für die Reproduktion von Konformationen in den Kristallstrukturen einer Tryparedoxin-Mutation untersucht. Anschließend wurden die getesteten Kraftfelder eingesetzt, um den Aktivitätsverlust bei der Mutation von drei Aminosäuren, die einen hydrophoben Schirm über dem aktiven Zentrum von Tryparedoxin bilden, zu erklären. Die in dieser Arbeit vorgestellten Untersuchungen haben es ermöglicht, die Möglichkeiten und Grenzen verschiedener computergestützten Berechnungsmethoden zum Verständnis der Enzymfunktionalität und zur Erleichterung der Arzneimittelforschung zu evaluieren. Darüber hinaus bieten sie Einblicke in die komplizierten Reaktionsmechanismen verschiedener Inhibitoren und die Funktionalität der Oxidoreduktase Tryparedoxin.