Simulations of Chemical Catalysis

This dissertation contains simulations of chemical catalysis in both biological and heterogeneous contexts. A mixture of classical, quantum, and hybrid techniques are applied to explore the energy profiles and compare possible chemical mechanisms both within the context of human and bacterial enzymes, as well as exploring surface reactions on a metal catalyst. A brief summary of each project follows. Project 1 — Bacterial Enzyme SpvC The newly discovered SpvC effector protein from Salmonella typhimurium interferes with the host immune response by dephosphorylating mitogen-activated protein kinases (MAPKs) with a -elimination mechanism. The dynamics of the enzyme substrate complex of the SpvC effector is investigated with a 3.2 ns molecular dynamics simulation, which reveals that the phosphorylated peptide substrate is tightly held in the active site by a hydrogen bond network and the lysine general base is positioned for the abstraction of the alpha hydrogen. The catalysis is further modeled with density functional theory (DFT) in a truncated active-site model at the B3LYP/6-31 G(d,p) level of theory. The truncated model suggested the reaction proceeds via a single transition state. After including the enzyme environment in ab initio QM/MM studies, it was found to proceed via an E1cB-like pathway, in which the carbanion intermediate is stabilized by an enzyme oxyanion hole provided by Lys104 and Tyr158 of SpvC. Project 2 — Human Enzyme CDK2 Phosphorylation reactions catalyzed by kinases and phosphatases play an indispensable role in cellular signaling, and their malfunctioning is implicated in many diseases. Ab initio quantum mechanical/molecular mechanical studies are reported for the phosphoryl transfer reaction catalyzed by a cyclin-dependent kinase, CDK2. Our results suggest that an active-site Asp residue, rather than ATP as previously proposed, serves as the general base to activate the Ser nucleophile. The corresponding transition state features a dissociative, metaphosphate-like structure, stabilized by the Mg(II) ion and several hydrogen bonds. The calculated free-energy barrier is consistent with experimental values. Project 3 — Bacterial Enzyme Anthrax Lethal Factor In this dissertation, we report a hybrid quantum mechanical and molecular mechanical study of the catalysis of anthrax lethal factor, an important first step in designing inhibitors to help treat this powerful bacterial toxin. The calculations suggest that the zinc peptidase uses the same general base-general acid mechanism as in thermolysin and carboxypeptidase A, in which a zinc-bound water is activated by Glu687 to nucleophilically attack the scissile carbonyl carbon in the substrate. The catalysis is aided by an oxyanion hole formed by the zinc ion and the side chain of Tyr728, which provide stabilization for the fractionally charged carbonyl oxygen. Project 4 — Methanol Steam Reforming on PdZn alloy Recent experiments suggested that PdZn alloy on ZnO support is a very active and selective catalyst for methanol steam reforming (MSR). Plane-wave density functional theory calculations were carried out on the initial steps of MSR on both PdZn and ZnO surfaces. Our calculations indicate that the dissociation of both methanol and water is highly activated on \ufb02at surfaces of PdZn such as (111) and (100), while the dissociation barriers can be lowered significantly by surface defects, represented here by the (221), (110), and (321) faces of PdZn. The corresponding processes on the polar Zn-terminated ZnO(0001) surfaces are found to have low or null barriers. Implications of these results for both MSR and low temperature mechanisms are discussed

Empirical Distribution Models for Slenderness and Aspect Ratios of Core Particles of Particulate Wood Composites

Particle geometry was characterized for particleboard furnish prepared through hydrolysis of finished commercial particleboard procured from six Canadian plants. Particles samples were screened into seven particle size classes. Particles retained on 0.5-mm mesh were considered core particles and further partitioned into core-fine, medium, and coarse. Individual particles were then randomly selected for geometrical characterization and distribution fitting. About 80% of all screened particles by mass were between mesh sizes of 0.5 and 2 mm. There were significant differences in percentage screen masses of all particle sizes between plants. Masses of particle size greater than 1 mm of panels from two plants were significantly higher than the rest (0.05 α-level), whereas another plant had the highest mass of particle sizes retained on the 2-mm mesh. Particles retained on the 1-mm mesh showed the largest percentage mass variation among all plants. It was found that aspect ratio was a better geometrical indicator for predicting screw withdrawal resistance than any of the absolute dimensions, and increase in core-fine particles increases internal bond strength. Based on maximum likelihood and Akaike's Information Criterion, a log normal distribution was the best fit for all geometrical descriptors of most particle types; gamma and two-parameter Weibull were better fits for length and aspect ratio for most medium particles with gamma being the better of the two

Double-Peaked Narrow-Line Active Galactic Nuclei. II. The Case Of Equal Peaks

Active galactic nuclei (AGNs) with double-peaked narrow lines (DPAGNs) may be caused by kiloparsec-scale binary AGNs, bipolar outflows, or rotating gaseous disks. We examine the class of DPAGNs in which the two narrow-line components have closely similar intensity as being especially likely to involve disks or jets. Two spectroscopic indicators support this likelihood. For DPAGNs from Smith et al., the "equal-peaked" objects (EPAGNs) have [Ne V]/[O III] ratios lower than for a control sample of non-double-peaked AGNs. This is unexpected for a pair of normal AGNs in a galactic merger, but may be consistent with [O III] emission from a rotating ring with relatively little gas at small radii. Also, [O III]/H beta ratios of the redshifted and blueshifted systems in the EPAGN are more similar to each other than in a control sample, suggestive of a single ionizing source and inconsistent with the binary interpretation.University Cooperative Society of the University of Texas at AustinJane and Roland Blumberg Cenntenial Professorship in AstronomyAlfred P. Sloan FoundationNational Aeronautics and Space AdministrationNational Science FoundationU.S. Department of EnergyJapanese MonbukagakushoMax Planck SocietyUniversity of ChicagoInstitute for Advanced StudyJapan Participation GroupJohns Hopkins UniversityKorean Scientist GroupLos Alamos National LaboratoryMax-Planck-Institute for Astronomy (MPIA)Max-Planck-Institute for Astrophysics (MPA)New Mexico State UniversityUniversity of PittsburghUniversity of PortsmouthPrinceton UniversityUnited States Naval ObservatoryUniversity of WashingtonFermilabAstronom

The Jet-Driven Outflow In The Radio Galaxy SDSS J1517+3353: Implications For Double-Peaked Narrow-Line Active Galactic Nucleus

We report on the study of an intriguing active galaxy that was selected as a potential multiple supermassive black hole merger in the early-type host SDSS J151709.20+335324.7 (z = 0.135) from a complete search for double-peaked [O III] lines from the SDSS spectroscopic quasi-stellar object (QSO) database. Ground-based SDSS imaging reveals two blue structures on either side of the photometric center of the host galaxy, separated from each other by about 5.7 kpc. From a combination of SDSS fiber and Keck/HIRES long-slit spectroscopy, it is demonstrated that, in addition to these two features, a third distinct structure surrounds the nucleus of the host galaxy. All three structures exhibit highly ionized line emission with line ratios characteristic of Seyfert II active galactic nuclei. The analysis of spatially resolved emission-line profiles from the HIRES spectrum reveal three distinct kinematic subcomponents, one at rest and the other two moving at -350 km s(-1) and 500 km s(-1) with respect to the systemic velocity of the host galaxy. A comparison of imaging and spectral data confirm a strong association between the kinematic components and the spatial knots, which implies a highly disturbed and complex active region in this object. A comparative analysis of the broadband positions, colors, kinematics, and spectral properties of the knots in this system lead to two plausible explanations: (1) a multiple active galactic nucleus (AGN) produced due to a massive dry merger, or (2) a very powerful radio jet-driven outflow. Subsequent VLA radio imaging reveals a clear jet aligned with the emission-line gas, confirming the latter explanation. We use the broadband radio measurements to examine the impact of the jet on the interstellar medium of the host galaxy, and find that the energy in the radio lobes can heat a significant fraction of the gas to the virial temperature. Finally, we discuss tests that may help future surveys distinguish between jet-driven kinematics and true black-hole binaries. J1517+3353 is a remarkable laboratory for AGN feedback and warrants deeper follow-up study. In the Appendix, we present high-resolution radio imaging of a second AGN with double-peaked [O III] lines, SDSS J112939.78+605742.6, which shows a sub-arcsecond radio jet. If the double-peaked nature of the narrow lines in radio-loud AGNs are generally due to radio jet interactions, we suggest that extended radio structure should be expected in most of such systems.NSF AST-0507483, AST-0808133University of Texas at AustinAlfred P. Sloan FoundationParticipating InstitutionsNational Aeronautics and Space AdministrationU.S. Department of EnergyJapanese MonbukagakushoMax Planck SocietyAstronom

The detection of subsurface stream channels in carbonate rocks by geoelectrical methods

Student supported: 1 Student AssistantThe distinction of partially dissolved from compact carbonate rocks and from the alluvial overburden is a major problem in geological engineering and water resources. Geoelectrical depth soundings after Schlumberger were applied over karst terraines in three locations of the Ozarks in Missouri. The zone of dissolved carbonate rock shows intermediate resistivities between low values for the overburden and extremely high values for the compact rock. The main part of the investigation was directed towards solving the underground flow and disappearance of Logan Creek near Ellington, Missouri. Combined geoelectrical and gravity surveys under consideration of some near surface seismic refractions indicate zones of increased depth and degree of dissolution at the Ellington Fault. A detailed gravity profile across the fault shows a negative anomaly with a minimum of -2.0 mgal, which extends over approximately 3 miles with large lateral gradients. A theoretical model can explain the anomaly if the depth of the cavernous limestone has a maximum of 350 feet and if the bulk volume of fissures and stream channels amounts to 15 percent. The coincidence between the fault and the negative anomaly suggests that ruptures along fault planes weakened the rock so that chemical dissolution from surface waters had a greater penetration.Project # A-065-MO Agreement # 14-31-0001-382

Mitoxantrone is superior to doxorubicin in a multiagent weekly regimen for patients older than 60 with high-grade lymphoma: results of a BNLI randomized trial of PAdriaCEBO versus PMitCEBO

A prospective, multicenter, randomized trial was undertaken to compare the efficacy and toxicity of adriamycin with mitoxantrone within a 6-drug combination chemotherapy regimen for elderly patients (older than 60 years) with high-grade non-Hodgkin lymphoma (HGL) given for a minimum of 8 weeks. A total of 516 previously untreated patients aged older than 60 years were randomized to receive 1 of 2 anthracycline-containing regimens: adriamycin, 35 mg/m2 intravenously (IV) on day 1 (n = 259), or mitoxantrone, 7 mg/m2 IV on day 1 (n = 257); with prednisolone, 50 mg orally on days 1 to 14; cyclophosphamide, 300 mg/m2 IV on day 1; etoposide, 150 mg/m2 IV on day 1; vincristine, 1.4 mg/m2 IV on day 8; and bleomycin, 10 mg/m2 IV on day 8. Each 2-week cycle was administered for a minimum of 8 weeks in the absence of progression. Forty-three patients were ineligible for analysis. The overall and complete remission rates were 78% and 60% for patients receiving PMitCEBO and 69% and 52% for patients receiving PAdriaCEBO (P = .05, P = .12, respectively). Overall survival was significantly better with PMitCEBO than PAdriaCEBO (P = .0067). However, relapse-free survival was not significantly different (P = .16). At 4 years, 28% of PAdriaCEBO patients and 50% of PMitCEBO patients were alive (P = .0001). Ann Arbor stage III/IV, World Health Organization performance status 2-4, and elevated lactate dehydrogenase negatively influenced overall survival from diagnosis. In conclusion, the PMitCEBO 8-week combination chemotherapy regimen offers high response rates, durable remissions, and acceptable toxicity in elderly patients with HGL

An endogenous F-box protein regulates ARGONAUTE1 in Arabidopsis thaliana

ARGONAUTE1 (AGO1) mediates microRNA- and small interfering RNA-directed posttranscriptional gene silencing in Arabidopsis thaliana. Mutant alleles of SQUINT (SQN) slightly reduce AGO1 activity and have weak effects on shoot morphology. A screen for mutations that suppress the sqn phenotype produced loss-of-function mutations in the F-box gene FBW2. Mutations in FBW2 not only suppress sqn but also suppress many of the developmental phenotypes of weak, but not null, alleles of AGO1 by increasing AGO1 protein levels. Conversely, over-expression of FBW2 decreases the abundance of the AGO1 protein but not AGO1 messenger RNA, further indicating that FBW2 regulates AGO1 protein levels. fbw2 mutants have no obvious morphological phenotype, but display a reduced sensitivity to abscisic acid (ABA) that can be attributed to increased AGO1 activity. Our results indicate that FBW2 is a novel negative regulator of AGO1 and suggest that it plays a role in ABA signalling and/or response

Prevalence and potential fitness cost of weak phosphine resistance in Tribolium castaneum (Herbst) in eastern Australia

The prevalence of resistance to phosphine in the rust-red flour beetle, Tribolium castaneum, from eastern Australia was investigated, as well as the potential fitness cost of this type of resistance. Discriminating dose tests on 115 population samples collected from farms from 2006 to 2010 showed that populations containing insects with the weakly resistant phenotype are common in eastern Australia (65.2 of samples), although the frequency of resistant phenotypes within samples was typically low (median of 2.3). The population cage approach was used to investigate the possibility that carrying the alleles for weak resistance incurs a fitness cost. Hybridized populations were initiated using a resistant strain and either of two different susceptible strains. There was no evidence of a fitness cost based on the frequency of susceptible phenotypes in hybridized populations that were reared for seven generations without exposure to phosphine. This suggests that resistant alleles will tend to persist in field populations that have undergone selection even if selection pressure is removed. The prevalence of resistance is a warning that this species has been subject to considerable selection pressure and that effective resistance management practices are needed to address this problem. The resistance prevalence data also provide a basis against which to measure management success