The M2 proton channel from Influenza A is an established drug target, with multiple functions during the viral lifecycle. Amino acid mutations, in the residues lining the channel pore, have rendered M2 resistant to previously licensed inhibitors. Given the propensity for genetic reassortment of Influenza A and history of pandemics due to emergence of novel human strains, M2 has been subject of numerous structural characterization efforts. Attempts at rational drug design targeting M2 proton channel have been impeded by the limited number of experimental techniques having capabilities for elucidating atomic level interactions of the protein-ligand complexes in the native-like membrane mimetic environment. Solid state Nuclear Magnetic Resonance (ssNMR) is a technique that has all of these capabilities for structural characterization of membrane protein drug targets in lipid bilayers. Coupling ssNMR with Computer Aided Drug Discovery (CADD) is the precise approach needed to decrease time and resources required to generate novel therapeutics. Here, we present a first structural characterization of the full length wild type M2 channel in complex with inhibitor, and of the S31N mutant in the apo and drug-bound state. Through the use of diverse ssNMR experiments we tested stereoselectivity of drug binding in the channel pore, structural changes due to mutation, and characterized novel inhibitor interactions. Molecular dynamic simulations were performed by our collaborators and were in good agreement with our experimental findings. Together these results deepen our understanding of the atomic level interactions stabilizing wild type inhibitors in the channel pore, and structural changes in the mutant leading to loss of compound efficacy. Most importantly, specific interaction described herein are essential for successful outcomes from structure based CADD and be used in future computational efforts. / A Dissertation submitted to the Institute of Molecular Biophysics in partial fulfillment of the Doctor of Philosophy. / Fall Semester 2015. / December 7, 2015. / Drug Discovery, Influenza A, M2, membrane proteins, NMR, solid state / Includes bibliographical references. / Timothy Cross, Professor Directing Dissertation; Gregory B. Dudley, University Representative; Michael Blaber, Committee Member; Alan G. Marshall, Committee Member; Thomas C. S. Keller, Committee Member.

The development and experimental validation of a mathematical model for nanoparticle–based surface energy transfer (SET) between gold nanoparticles and fluorescent dye labels, has enabled biophysical studies of nucleic acid structure and function previously inaccessible by other methods. The main advantages of SET for optical distance measurements are that it can operate over longer distances than other similar methods, such as Forster Resonance Energy Transfer (FRET), thus enabling measurements across biological structures much larger than otherwise possible. This work discusses the fundamental theory for the SET interaction and expansion of SET theory to account for multiple interacting dye labels and demonstrated on DNA and RNA in order to allow 3D triangulation of labeled structures. SET theory has also been expanded to core@shell structures which represent a new class of designer SET platforms with dramatically increased spectral windows; allowing for a multitude of dye labels to be used simultaneously over a broad range of wavelengths. Additionally, these designer nanostructures can incorporate the material properties of the core. So that , for example Ni@Au, can provide a SET measurement platform coupled with a magnetic moment for sample purification and manipulation. These efforts to develop and establish optical SET methods lays a foundation of a powerful methodology for biophysical characterization, and allows researchers to study biological structures previously too large or complex to be easily studied, such as the unknown tertiary structures of large RNA elements. / A Dissertation submitted to the Institute of Molecular Biophysics in partial fulfillment of the requirements for the degree of Doctor of Philosophy. / Summer Semester 2016. / June 28, 2016. / DNA, Energy Transfer, Nanoparticles, Optical Ruler, RNA / Includes bibliographical references. / Geoffrey F. Strouse, Professor Directing Dissertation; Richard L. Hyson, University Representative; Piotr G. Fajer, Committee Member; M. Elizabeth Stroupe, Committee Member; Hank W. Bass, Committee Member.

This thesis describes the application of wave function-based and perturbative methods to extended systems, primarily semiconductors. In Chapter 1, I introduce the quantum chemistry problem along with current progress in the field. I then provide some requisite fundamental theory associated with the wave function-based methods and periodic boundary conditions. In Chapter 2, I describe the relationship between the traditional extended system GW method and the traditionally molecular coupled-cluster formalism through diagrammatic analysis. We find that the popular coupled cluster singles and doubles (CCSD) method contains most of the diagrams in GW theory and more, and the more accurate coupled cluster singles and doubles with perturbative triples (CCSD(T)) method contains all GW diagrams and more. Benchmarking on the GW100 test set indicates that CCSD and a number of its approximations are more accurate than GW theory. In Chapter 3, I evaluate the potential for using composite schemes to reduce the computational cost of the CCSD method. We use focal point and downfolding techniques for excited state results for the GW100 along with some sample solids. Using composite methods reduces the cost of CCSD by reducing the number of orbitals treated at a higher level of theory, which is very similar to the active space methods used in single- and multi-reference calculations. In Chapters 4 and 5, I describe how to best treat finite size effects for wave function-based methods, including the impact of including terms like the Madelung constant and which extrapolation form to use. After establishing this, we use the prescribed procedure to compare the equation-of-motion second-order M{\o}ller-Plesset (EOM-MP2) method to the MP2 method of Gr\"{u}neis and the GW method for a standard test set of 11 solid-state systems. We find that the MP2 method performs qualitatively and quantitatively poorly for extended systems, but EOM-MP2 and GW perform qualitatively well, with quantitative MAEs of 0.40 and 0.68eV, respectively relative to a zero-point corrected electronic band gap.

Ph.D, Faculty of Science, University of the Witwatersrand, 2011 / Investigations into methane conversion (both catalytic and non-catalytic) and characterization of the carbon produced for use in high efficiency DCFCs were performed. Under non-catalytic processes, a high methane conversion (> 80%) was achieved at 1200 oC at flow rates of between 10-60 ml/min. Analysis of the carbon using Raman spectroscopy showed that the carbon was highly disordered and the degree of disorder increased with increase in methane flow rate (from aD/aG = 1.54 at 10 ml to aD/aG = 2.24 at 60 ml/min). Further analysis of the carbon using thermogravimetric analysis (TGA) demonstrated that the carbon produced at higher flow rates e.g. 100 ml/min were easily oxidized (746 oC) compared with those produced at lower flow rates (10 ml/min, 846 oC). Therefore, a high temperature coupled with high flow rates (60-100 ml/min) produced carbon with desired qualities (high disorder, low crystallinity and more thermally reactive) for DCFC uses. In the catalytic decomposition of methane, Ni supported on TiO2 and a 1:1 mixture of TiO2/Al2O3 gave high and stable methane conversions of about 60% at only 600 oC compared to 1200 oC required for the non-catalytic conversion. These catalysts were found to be the best catalyst systems of the tested catalysts. Considering the thermal oxidation and crystallinity data which are some of the properties of the carbon required for direct carbon fuel cells (DCFCs), the carbon produced can potentially be used in DCFC systems.

No description available.

No description available.

In recent years, advances in computer technology combined with new ab initio computational methods have allowed for dramatic improvement in the prediction of energetic properties. Unfortunately, even with these advances, the extensive computational cost, in terms of computer time, memory, and disk space of the sophisticated methods required to achieve chemical accuracy - defined as 1 kcal/mol from reliable experimental data effectively - limits the size of molecules [i.e. less than 10-15 non-hydrogen atoms] that can be studied. Several schemes were explored to help reduce the computational cost while still maintaining chemical accuracy. Specifically, a study was performed to assess the accuracy of ccCA to compute atomization energies, ionization potentials, electron affinities, proton affinities, and enthalpies of formation for third-row (Ga-Kr) containing molecules. Next, truncation of the correlation consistent basis sets for the hydrogen atom was examined as a possible means to reduce the computational cost of ab initio methods. It was determined that energetic properties could be extrapolated to the complete basis set (CBS) limit utilizing a series of truncated hydrogen basis sets that was within 1 kcal/mol of the extrapolation of the full correlation consistent basis sets. Basis set truncation for the hydrogen atom was then applied to ccCA in the development of two reduced basis set composite methods, ccCA(aug) and ccCA(TB). The effects that the ccCA(aug) and ccCA(TB) methods had upon enthalpies of formation and the overall percent disk space saved as compared to ccCA was examined for the hydrogen containing molecules of the G2/97 test suite. Additionally, the Weizmann-n (Wn) methods were utilized to compute the several properties for the alkali metal hydroxides as well as the ground and excited states of the alkali monoxides anion and radicals. Finally, a multi-reference variation to the correlation consistent Composite Approach [MR-ccCA] was presented and utilized in the computation of the potential energy surfaces for the N2 and C2 molecules.

We have modeled in one-dimension two-dimensional (2-D) quantum wire structures: the notched electron stub tuner (NEST) and the double-notched electron stub tuner (D-NEST). The models consisted of square barriers representing the notches and square wells representing the stubs. We have calculated the transmission coefficient as a function of electron energy and/or device geometries to study electron transport through these quantum wire models. The transfer matrix method was used to calculate the transmission coefficient by utilizing a program written with Mathematica. The program and technique were verified using one-dimensional systems from the literature.We studied the principle of wave interference in the NEST model in the form of intersection points of several curves of the transmission coefficient versus barrier/well separation plotted with no offset. The creation of standing waves, in certain regions of the NEST model, by the interference of incident and reflected waves, gives rise to these intersection points. We have identified features in the conductance curves of the NEST and the transmission coefficient curves of the NEST model (the intersection points) that are very similar and may be explained by the same principle of wave interference.We have studied double-barrier resonant tunneling (DBRT) to assist in our study of the D-NEST model. The resonances in DBRT are attributed to the creation of standing waves between the two barriers for the tunneling and non-tunneling regimes. We attempted to prove the existence of these standing waves by studying the probability density in the D-NEST model. The well of the D-NEST model was scanned down the length of the double-barrier well region to investigate its effect on the transmission coefficient for this purpose. A small square barrier, used as a probe, was also used to study the probability density in the same way as the well was used. Initial scans of the probe above a simple square barrier gave us insight into the possibility of using it to scan for the probability density in the well region. The "over-the-barrier" resonances (attributed to standing waves) were studied in this case.We have developed knowledge of the transmission properties of these models that may aid in the understanding of the electron transport through the 2-D devices. We believe that to "fine tune" the conductance output of the D-NEST device, the second notch should be placed at a location that permits the creation of standing waves, for a specific electron energy value, between the two notches of the device. The "fine tuning" of the conductance output into a square-wave pattern could improve the devices performance as a potential switching mechanism. / Department of Chemistry

LD2668 .T4 1962 P36

LD2668 .T4 1962 K68