Recent experimental studies have shown unexpected chiroptical response from some chiral surfactant molecules. In these cases, the magnitude of the specific optical rotation was seen to change as a function of surfactant concentration, which is considered to be due to molecular aggregation and contrary to that known for typical organic molecules. To explain these experimental results on the +10,000 atom surfactant systems, non-traditional methods are necessary. To that end, a large number of molecular dynamics simulations, quantum mechanical calculations, and extensive analysis have been performed on a model system, the lauryl ester of phenylalanine. Monomer-dimer equilibrium, representing the simplest form of aggregation, and its influence on the Horeau effect, have also been investigated using pantolactone and 2-hydroxy-3-pinanone as test cases. Also a novel chiroptical spectral analysis method utilizing the Dissymmetry Factor (DF) spectrum has been developed. Studies ranging from rigid to flexible molecules have demonstrated the advantages of the DF method, especially when several diastereomers are involved. Using the DF spectrum as an additional means of analysis, the previously undetermined absolute configurations of four natural products have been determined.

Computational design of protein-ligand interfaces expands understanding of the basic forces involved in molecular recognition, and also contributes to the development of protein therapeutics. My dissertation research contributes to this body of knowledge through a series of Specific Aims. Specific Aim 1 involves screening a diverse set of small molecules for intrinsic binding affinity to my protein, HisF. 28 binding ligands were identified by using nuclear magnetic resonance (NMR) techniques by tracking chemical shift peaks. This also allows us to calculation dissociation constants, which ranged between 340 â 1110 µM. These binding ligands were then computationally docked into HisF using RosettaLigand of the Rosetta modeling suite. Computational results were compared to the experimental data to identify strengths/weaknesses of the program. These results are the focus of Chapter 3, âExperimental and Computational Identification of Naïve Binders to a TIM-Barrel Protein Scaffoldâ (first author), to be submitted soon. Specific Aim 2 involved optimizing RosettaLigand to design proteins that bind small molecules. The software was tested for accuracy and efficiency using a set of protein-ligand crystal structures, and these results are the focus of my 2014 published manuscript and Chapter 2, âComputational Design of Protein-Small Molecule Interfacesâ (first author). A detailed description of how to utilize RosettaLigand is the focus of Chapter 4, âRosetta and Design of Ligand Binding Sitesâ (secondary author), manuscript accepted. Specific Aim 3 combines the first two aims, to redesign the protein interface to bind the small molecules more tightly than the wild type protein. We have used RosettaLigand to redesign HisF to bind one VU0068924 more tightly, with binding affinity improving from 442 µM to 23 µM. This is the focus of Appendix C âDesigned C9S_HisF Binds VU0068924 More Tightlyâ, and will be the focus of a future manuscript. For each project, the protocols, scripts, command-lines, experiments not described in the manuscript are included in the appendix. The models, code, scripts, and figures are included in the thesis directory that accompanies the thesis.

The rational design of hybrid nanoparticles is a powerful tool in harnessing nanoscale properties of several different materials in a single whole. The first portion of this work describes the synthesis of dual-plasmonic hybrid gold-copper sulfide nanoparticles for application in the enhancement of second harmonic generation of light. Established synthetic methods were applied to create hybrid nanoparticle systems that contained two separate localized surface plasmon resonances. The second portion of this work describes the synthesis of gold sulfide nanoparticles via a cation exchange procedure with copper sulfide nanoplatelets. The growing significance of the copper sulfides as a nontoxic alternative to commercially significant quantum dot materials such as PbS and CdS has led to a proliferation of work studying these materials. However, Au2S, a material with potential for many of the same applications as Cu2S, remains relatively ignored. The inherent difficulty of direct synthesis of gold (I) sulfide in the nanocrystalline form as well as the metastable nature of the material once synthesized are significant obstacles to the study of Au2S. We report an indirect synthesis of Au2S nanocrystals and Au2SâCu2-xS hybrid nanoparticles via cation exchange, and the insights into this material transformation gained in this study.

The star-like molecule, 2, 7-diamino-9,9-bis(4-aminophenyl)fluorene, was used to effectively control the orientation of linear polyimide chains so as to prepare star-like polyimide systems that are excellent candidates of improved compressive properties compared to the linear analogues. The synthesis of the central fluorene unit involved the reaction of 2,7-dinitro-9-fluorenone with aniline in the presence of aniline hydrochloride followed by the reduction of the nitro functionalities. The incorporation of this favorable geometric molecule by condensation with the C-terminus of the linear polyimides resulted in the synthesis of three-dimensional polyimides. Polyimide systems exhibiting improved solubility in organic solvents and strong acids, and transitions at lower temperatures were prepared by introducing hexafluoro groups (bis-4,4’-aminophenylhexafluoropropane and 4,4’-(hexafluoroisopropylidene)diphthalic anhydride), and by using a dianhydride (bicyclo[2.2.2]oct-7-ene-2,3,5,6-tetracarboxylic dianhydride) with reduced symmetry and decreased π-electron density relative to benzene tetracarboxylic dianhydride. An improvement in the solubility of the thermally stable three-dimensional polyimides was observed as a result of a decrease in linearity and an increase in free volume due to the star-like structure of the three-dimensional polyimides.

Zeolites, having stable porous structures and high ion exchange capabilities are potential buffer materials that can be added to a soil matrix to improve the ion exchange ability. This study investigated the performance of various zeolites for the uptake of uranium as soluble UO22+, with the ultimate goal being to develop an in situ ion trap to immobilize potentially leachable residue in uranium contaminated soils. The natural zeolite, clinoptilolite and synthetic zeolites, K-L, LZY, 13X, and mordenite were evaluated for the uptake of UO22+ in both batch and column percolation studies. In the preliminary batch and column studies, mordenite, LZY, and K-L were most effective for uranium uptake. The pH was an important factor in governing which uranium species would be present in solution. In the pH controlled batch studies, mordenite demonstrated superior performance to the other zeolites as well as to a clay-soil for uranium uptake. With time, initially absorbed uranium was dissolved from the soil into solution whereas the zeolite showed no such release of uranium. Uranium uptake was found to be dependent on zeolite pore size, solution pH, cation concentrations, and amount of sorbent

New and innovative materials are needed to develop more effective batteries. Nanoscale materials such as graphite have unique properties only seen in the nano-regime that allow them to be used in the production of lithium-ion batteries. For example, because of its ability to conduct electricity, nano-scale graphite has been used in the anode of lithium-ion batteries, which has revolutionized the long-term use of medical devices, such as pacemakers and defibrillators. Interestingly, the graphite anode has a relatively low specific capacity per gram of ~372 mAh g-1, which limits the rate of charge available to these devices. The specific capacity of silicon, however, is ~11 times greater than that of graphite at ~4200 mAh g-1, which makes it a better choice as an anode material. Silicon is not presently used because of its fragility during the lithiation process. In this work, we demonstrate a robust nanoscale material synthesis inspired by the biomineralization process that the ocean-dwelling unicellular phytoplankton, diatoms, that they use to form their porous silicon structure. By maintaining the porous structure of diatoms from the conversion of silica to silicon, using a magnesiothermic reduction process, their structure can be used to enhance siliconâs strength during the lithiation process allowing the use of siliconâs higher specific capacity. This approach has the potential to implement silicon as an anode for lithium-ion batteries to enhance the longevity of present day applications.

N6-(Deoxy-D-Erythro-Pentofuranosyl)-2,6-Diamino-3,4-Dihydro-4-Oxo-5-N-Methylformamido-Pyrimidine (MeFapy-dG) is a deoxyribonucleic acid lesion that has been hypothesized to be induced by methylating chemotherapeutic agents. MeFapy-dG is known to block DNA replication, ultimately leading to a diverse mutagenic profile dependent on the sequence context. 8-(Deoxyguanosin-N2-yl)-1-Aminopyrene (N2-AP-dG) is a bulky DNA adduct that is a product of 1-nitropyrene (1-NP) nitroreduction. 1-NP is a prevalent chemical carcinogen found in diesel exhaust, coal fly ash, and other environmental pollutants. Previous research demonstrated that N2-AP-dG stalls replication with Dpo4 with the potential to induce various mutations. Both MeFapy-dG and N2-AP-dG were studied in the structural context using Nuclear Magnetic Resonance Spectroscopy (NMR). In the case of MeFapy-dG, important cross-peaks were located in the NMR spectra providing structural evidence of the ?- and ?-anomers, indicating that both populations were present in solution. Furthermore, the N2-AP-dG unmodified duplex was characterized, demonstrating that the unmodified sequence context adopted normal B-type DNA. The modified N2-AP-dG NMR spectra provided evidence that the adduct was oriented in the minor groove of the DNA duplex, pointing in the 3â direction of the modified strand, with minimal perturbation of the global DNA structure.

The polymerization of glycidol has been studied for some time due to the numerous uses for the product polymer species, including the transportation of drug molecules and biological cargo, biomineralization, and even solid catalyst supports in organic synthesis. Hitherto, the entirety of research performed has been restrained to the formation of either hyperbranched dendrimer-like structures through either cationic or anionic polymerization mechanisms, or solely linear species through the polymerization of protected derivatives with subsequent deprotection steps. The product structures are limited in their post-modification potential to reactions based around the functionalization of the numerous pendant hydroxyl groups. The dendrimer-like structures are limited to implementation of the products in problems previously treated by dendrimer species, while the rigorous reaction conditions and numerous protection and deprotection steps that facilitate the formation of the linear species are far from what could be considered facile. The advent of novel synthetic routes to take advantage of the inherent water solubility of poly(glycidol) systems and development of methodologies to prepare poly(glycidol)s that address the need for controlled semibranched structures for implementation in the study of diverse biomedical research targets is presented. The newly synthesized structures afford a polymerization pathway that can be performed on the bench top with little extraneous concern for reaction conditions. The utilization of a previously studied tin catalyst provides a reproducible and facile method for the formation of semi-branched polyglycerol structures. Further investigation has also led to the formulation of a completely green synthetic route that can be utilized in the formation of poly(glycidol) and the functionalization of biological proteins such as BSA and LYZ. The synthesis routes utilized allow for the introduction of functional groups during the polymerization process, which leads to the ability for inclusion of the newly formed polymer structures, in conjunction with polymers previously pioneered in the lab, for the development of a novel pathway for the formation of monodisperse microgel structures, using a readily available materials printer system, capable of delivering both hydrophobic and hydrophilic therapeutic cargo.

Malaria is an entirely preventable and treatable disease, yet it is endemic in nearly half of the countries around the world. One of the most important drug targets for this disease is the hemozoin formation pathway, a heme detoxification process found in the malaria parasite. In the search for novel hemozoin inhibitors, we developed a target based assay that closely mimics the biological conditions and screened three compound libraries. Hits were then tested in a phenotypic screen for antiplasmodial activity. These experiments, however, do not provide the information required to fully comprehend the in vivo drug mechanism of action. To validate hemozoin inhibition, we analyzed three types of parasitic heme: hemoglobin, intracellular free heme, and hemozoin. Compounds were confirmed hits upon observation of a rise in free heme and a decrease in hemozoin percentage, corresponding to parasite death. Our screening efforts resulted in high hit rates compared to other β-hematin inhibition assays. To explain this discrepancy, we examined the physiochemical properties required for β-hematin formation using detergents as models for lipids within the digestive vacuole. A longer hydrophilic tail on the detergents allowed for more efficient heme sequestration and solubilization in lipophilic regions, which formed hemozoin-like crystals. Furthermore, even though drug resistance is climbing as the parasite adapts to antimalarial treatment, the hemozoin formation pathway is still a valid target since the mechanism of inhibition is separate from the mechanism of resistance. Hemozoin inhibitors bind to the µ-oxo heme dimer, preventing crystallization throughout the ring stage of the parasite life cycle, when hemozoin begins to form as a result of hemoglobin degradation. However, the location and exact mechanism of heme-drug interaction may vary among hemozoin inhibitors. Additionally, we investigated how these compounds specifically interact with their biological target using fluorescent probes. In drug discovery, it is not only important to find molecules that possess in vitro antimalarial activity, but also to understand how drugs interact with their biological target in order to aid in compound optimization.

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