Computational chemistry has led to the greater understanding of the molecular world, from the interaction of molecules, to the composition of molecular species and materials. Of the families of computational chemistry approaches available, the main families of electronic structure methods that are capable of accurate and/or reliable predictions of energetic, structural, and spectroscopic properties are ab initio methods and density functional theory (DFT). The focus of this dissertation is to improve the accuracy of predictions and computational efficiency (with respect to memory, disk space, and computer processing time) of some computational chemistry methods, which, in turn, can extend the size of molecule that can be addressed, and, for other methods, DFT, in particular, gain greater insight into which DFT methods are more reliable than others. Much, though not all, of the focus of this dissertation is upon transition metal species – species for which much less method development has been targeted or insight about method performance has been well established. The ab initio approach that has been targeted in this work is the correlation consistent composite approach (ccCA), which has proven to be a robust, ab initio computational method for main group and first row transition metal-containing molecules yielding, on average, accurate thermodynamic properties, i.e., within 1 kcal/mol of experiment for main group species and within 3 kcal/mol of experiment for first row transition metal molecules. In order to make ccCA applicable to systems containing any element from the periodic table, development of the method for second row transition metals and heavier elements, including lower p-block (5p and 6p) elements was pursued. The resulting method, the relativistic pseudopotential variant of ccCA (rp-ccCA), and its application are detailed for second row transition metals and lower p-block elements. Because of the computational cost of ab initio methods, DFT is a popular choice …
Glutathione syntethase (GS) is an enzyme that belongs to the ATP-grasp superfamily and catalyzes the second step in the biosynthesis of glutathione. GS has been purified and sequenced from a variety of biological sources; still, its exact mechanism is not fully understood. Four highly conserved residues were identified in the binding site of human GS. Additionally, the G-loop residues that close the active site during catalysis were found to be conserved. Since these residues are important for catalysis, their function was studied computationally by site-directed mutagenesis. Starting from the reported crystal structure of human GS, different conformations for the wild type and mutants were obtained using molecular dynamics technique. The key interactions between residues and ligands were detected and found to be essential for enzyme activity.
Employing correlation consistent basis sets coupled with electronic structure methods has enabled accurate predictions of chemical properties for second- and third-row main group and transition metal molecular species. For third-row (Ga-Kr) molecules, the performance of the correlation consistent basis sets (cc-pVnZ, n=D, T, Q, 5) for computing energetic (e.g., atomization energies, ionization energies, electron and proton affinities) and structural properties using the ab initio coupled cluster method including single, double, and quasiperturbative triple excitations [CCSD(T)] and the B3LYP density functional method was examined. The impact of relativistic corrections on these molecular properties was determined utilizing the Douglas-Kroll (cc-pVnZ-DK) and pseudopotential (cc-pVnZ-PP) forms of the correlation consistent basis sets. This work was extended to the characterization of molecular properties of novel chemically bonded krypton species, including HKrCl, FKrCF3, FKrSiF3, FKrGeF3, FKrCCF, and FKrCCKrF, and provided the first evidence of krypton bonding to germanium and the first di-krypton system. For second-row (Al-Ar) species, the construction of the core-valence correlation consistent basis sets, cc-pCVnZ was reexamined, and a revised series, cc-pCV(n+d)Z, was developed as a complement to the augmented tight-d valence series, cc-pV(n+d)Z. Benchmark calculations were performed to show the utility of these new sets for second-row species. Finally, the correlation consistent basis sets were used to study the structural and spectroscopic properties of Au(CO)Cl, providing conclusive evidence that luminescence in the solid-state can be attributed to oligomeric species rather than to the monomer.
Article discussing molecules, mechanisms, and materials and current applications of computational chemistry in the Journal of the American Chemical Society (JACS).
Data management plan for the grant "Development of Novel Approaches to Earth-abundant Methane Catalysis." Research on catalytic cycles for C–H activation and functionalization of light alkanes based on the CMD (concerted metalation deprotonation) mechanism will be modeled for Earth-abundant metal dicarboxylates and related complexes. The impact of inner and outer coordination sphere effects upon catalytic cycles for light alkane functionalization will be assessed using computational chemistry techniques. The aforementioned studies will be leveraged to identify promising, synthetically feasible lead catalysts for experimental collaborators.
This work discusses applications of computational simulations to enzymatic systems with a particular focus on the effects of various small perturbations on cancer and disease-related systems. First, we cover the development of carbohydrate-based PET imaging ligands for Galectin-3, which is a protein overexpressed in pancreatic cancer tumors. We uncover several structural features for the ligands that can be used to improve their binding and efficacy. Second, we discuss the AlkB family of enzymes. AlkB is the E. coli DNA repair protein for alkylation damage, and has human homologues with slightly different functions and substrates. Each has a conserved active site with a catalytic iron and a coordinating His...His...Asp triad. We have applied molecular dynamics (MD) to investigate the effect of a novel single nucleotide polymorphism for AlkBH7, which is correlated with prostate cancer and has an unknown function. We show that the mutation leads to active site distortion, which has been confirmed by experiments. Thirdly, we investigate the unfolding of hen egg white lysozyme in 90% ethanol solution and low pH, to show the initial steps of unfolding from a native-like state to the disease-associated beta-sheet structure. We compare to mass spectrometry experiments and also show differing pathways based on protonation state. Finally, we discuss three different DNA polymerase systems. DNA polymerases are the primary proteins that replicate DNA during cell division, and have various extra or specific functions. We look at a proofreading-deficient DNA polymerase III mutant, the effects of solvent on DNA polymerase IV's ability to bypass bulky DNA adducts, and a variety of mutations on DNA polymerase kappa.
This dissertation details the use of computational methods to understand the effect that cancer-related mutations have on proteins that complex with nucleic acids. Firstly, we perform molecular dynamics (MD) simulations of various mutations in DNA polymerase κ (pol κ). Through an experimental collaboration, we classify the mutations as more or less active than the wild type complex, depending upon the incoming nucleotide triphosphate. From these classifications we use quantum mechanics/molecular mechanics (QM/MM) to explore the reaction mechanism. Preliminary analysis points to a novel method for nucleotide addition in pol κ. Secondly, we study the ten-eleven translocation 2 (TET2) enzyme in various contexts. We find that the identities of both the substrate and complementary strands (or lack thereof) are crucial for maintaining the complex structure. Separately, we find that point mutations within the protein can affect structural features throughout the complex, only at distal sites, or only within the active site. The mutation's position within the complex alone is not indicative of its impact. Thirdly, we share a new method that combines direct coupling analysis and MD to predict potential rescue mutations using poly(ADP-ribose) polymerase 1 as a model enzyme. Fourthly, we perform MD simulations of mutations in the protection of telomeres 1 (POT1) enzyme. The investigated variants modify the POT1-ssDNA complex dynamics and protein—DNA interactions. Fifthly, we investigate the incorporation of remdesivir and other nucleotide analogue prodrugs into the protein-RNA complex of severe acute respiratory syndrome-coronavirus 2 RNA-dependent RNA polymerase. We find evidence for destabilization throughout the complex and differences in inter-subunit communication for most of the incorporation patterns studied. Finally, we share a method for determining a minimum active region for QM/MM simulations. The method is validated using 4-oxalocrotonate, TET2, and DNA polymerase λ as test cases.
Presentation for the 2010 University Scholars Day at the University of North Texas discussing quantum mechanical prediction of the existence of rare gas-bound species.
Undergraduate thesis on the emission of atmospheric pollutants. The pollutants focused on are NO and NO₂. The author discusses the influence of sulfur on NO emission using computational chemistry.
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).
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 …
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