1974 — 1977 |
Dawson, John [⬀] |
N/AActivity Code Description: No activity code was retrieved: click on the grant title for more information |
Computing Simulation of Plasmas @ University of California-Los Angeles |
0.958 |
1975 — 1977 |
Fried, Burton [⬀] Dawson, John (co-PI) [⬀] |
N/AActivity Code Description: No activity code was retrieved: click on the grant title for more information |
A Theoretical Study of Plasma Physics @ University of California-Los Angeles |
0.958 |
1977 — 1981 |
Dawson, John [⬀] Tajima, Toshiki (co-PI) [⬀] |
N/AActivity Code Description: No activity code was retrieved: click on the grant title for more information |
Computer Simulation of Plasmas @ University of California-Los Angeles |
0.958 |
1978 — 1980 |
Dawson, John [⬀] |
N/AActivity Code Description: No activity code was retrieved: click on the grant title for more information |
Numerical Studies of Magnetohydrodynamic Processes in Space @ University of California-Los Angeles |
0.958 |
1979 — 1990 |
Dawson, John [⬀] |
N/AActivity Code Description: No activity code was retrieved: click on the grant title for more information |
Spectroscopic Studies of Cytochrome P-450 @ University of South Carolina At Columbia |
0.958 |
1980 — 1986 |
Kennel, Charles (co-PI) [⬀] Dawson, John [⬀] |
N/AActivity Code Description: No activity code was retrieved: click on the grant title for more information |
Numerical Studies of Magnetohydrodynamics Processes in Space @ University of California-Los Angeles |
0.958 |
1981 — 1999 |
Lin, Anthony Dawson, John [⬀] |
N/AActivity Code Description: No activity code was retrieved: click on the grant title for more information |
Computer Simulation of Plasmas At Ucla @ University of California-Los Angeles |
0.958 |
1982 — 1983 |
Lin, Anthony Dawson, John (co-PI) [⬀] |
N/AActivity Code Description: No activity code was retrieved: click on the grant title for more information |
Computer Simulations of Free Electron Lasers Operated in Collective Mode @ University of California-Los Angeles |
0.958 |
1983 — 1985 |
Dawson, John [⬀] |
N/AActivity Code Description: No activity code was retrieved: click on the grant title for more information |
Computer Simulation of Plasmas At U C L a (Physics) @ University of California-Los Angeles |
0.958 |
1983 — 1986 |
Lin, Anthony Dawson, John (co-PI) [⬀] |
N/AActivity Code Description: No activity code was retrieved: click on the grant title for more information |
Computer Simulations of Radiation Generation From Relativistic Electron Beams (Electrical Engineering) @ University of California-Los Angeles |
0.958 |
1985 — 1987 |
Dawson, John [⬀] |
N/AActivity Code Description: No activity code was retrieved: click on the grant title for more information |
A Plasma Booster For Linear Accelerators (Physics) @ University of California-Los Angeles |
0.958 |
1985 — 1995 |
Dawson, John H [⬀] |
R01Activity Code Description: To support a discrete, specified, circumscribed project to be performed by the named investigator(s) in an area representing his or her specific interest and competencies. |
Spectroscopy and Mechanisms of Heme-Iron Oxygenases @ University of South Carolina At Columbia |
0.916 |
1985 — 1987 |
Dawson, John H [⬀] |
K04Activity Code Description: Undocumented code - click on the grant title for more information. |
Heme-Iron Mono-Oxygenases: Spectroscopy and Mechanism @ University of South Carolina At Columbia
This proposal presents a program of spectroscopic studies of porphyrin model complexes with magnetic circular dichroism (MCD) spectroscopy and of spectroscopic and mechanistic studies of four oxygen and peroxide metabolizing heme iron proteins: cytochrome P-450, secondary amine mono-oxygenase (SAMO), indoleamine dioxygenase (IDO) and chloroperoxidase (CPO). There are three overall objectives: (1) By investigating model porphyrin and heme protein ligand complexes of defined structure, the utility of MCD spectroscopy as a probe of heme iron electronic and ultimately, physical structure will be ascertained. We will examine synthetic Fe+3 (porph)(RS-)(X) and Fe+2 (porph)(X)(CO) complexes with variable biomimetic legands, X. In addition, we will study Fe+2/+3 (porph) imidazolate complexes and unusual six-coordinate high-spin Fe+3 porphyrin complexes. Experiments with heme iron complexes are designed to extablish spectroscopic fingerprints for each ligand and/or complex type for use in structure determination. We will also examine zinc porphyrin complexes where the effects of axial ligation can be more directly assessed. Next we will investigate IDO, CPO and SAMO and their ligand complexes in an effort to better define their coordination structure. (2) Studies designed to define the sturctural requirements for heme iron catalyzed hydroxylation of organic substrates by further characterization of the active site structures of P-450 and SAMO will be carried out. Studies from our laboratory indicate that they have different metal ion environments and that SAMO differs from myoglobin as well. Spectroscopic studies designed to better define its legand environment will continue. The sixth ligand to ferric P-450 may be an oxygen donor; to look for direct evidence for a water ligand, we will examine its EPR spectrum in 170 labelled water. Using a specific inhibitor, we will attempt to trap-out the key hydroxylation intermediate just beyond oxy-P-450. With NMR spectroscopy we will also try to define the distance relationship between the cnetral iron and the substrate. (3) We will test current hypotheses about the mechanism of N-dealkylation of P-450 and SAMO by doing 180 labelling experiments with substrates that form stable carbinolamine and related products rather than dealkylating. The stable product can then be tested for label incorporation from either dioxygen or water.
|
0.916 |
1985 — 1992 |
Dawson, John [⬀] |
N/AActivity Code Description: No activity code was retrieved: click on the grant title for more information |
Computer Simulation of Plasmas At Ucla (Physics) @ University of California-Los Angeles
This program has pioneered the use of computer modeling for investigating the physics of plasmas. The program is based on the philosophy of using computer simulation as a general tool to gain fundamental understanding of plasmas, to explore phenomena which are difficult or impossible to investigate in other ways, and to study interesting and potentially useful plasma behavior. A two year program is proposed to pursue studies of basic plasma physics, to investigate properties of plasma lenses and accelerators, to investigate the use of plasmas as radiation sources, to study dynamic Debye clouds in magnetized plasmas, to investigate lasing mechanisms which may have been operative in the early universe, and to develop diagnostic tools for plasma research.
|
0.958 |
1986 — 1990 |
Dawson, John [⬀] |
N/AActivity Code Description: No activity code was retrieved: click on the grant title for more information |
Plasma Applications For High Energy Physics @ University of California-Los Angeles |
0.958 |
1986 — 1996 |
Kennel, Charles (co-PI) [⬀] Pritchett, Philip Dawson, John [⬀] Wu, Cheng-Chin |
N/AActivity Code Description: No activity code was retrieved: click on the grant title for more information |
Numerical Studies of Magnetospheric Dynamics and Related Space Plasma Processes @ University of California-Los Angeles
This proposal is for numerical studies of the magnetosphere with a focus on the properties of intermediate shock waves, the dynamics of the magnetosheath and magnetopause, reconnection and convection in the geomagnetic tail, and auroral electron acceleration by lower-hybrid wave turbulence. Scaling behavior of intermediate shocks will be handled through magnetohydrodynamics (MHD) followed by hybrid simulations extended to the high ion beta case (beta is the ratio of plasma to field energy density). MHD studies of the magnetopause will be pursued along with hybrid models to study magnetopause structure. 3D global simulations will be done including all the large-scale dynamics of the magnetosphere to test the effects of magnetosheath and magnetopause boundary conditions. Response of the magnetosphere to these inputs will be analyzed through studies of collisionless reconnection in the near- Earth plasma sheet, extended to cover more general aspects of convection and to consider the structure and stability of more distant parts of the tail current sheet. A new high beta drift- kinetic simulation code will be developed including some kinetic effects for the electrons as well as ions. This code will be used to test the hypothesis that chaotization of electron orbits can restore the universal ion tearing mode - a fundamental question for the reconnection process in space plasmas. Resonant electron acceleration by ion wave turbulence will be studied and the results compared with observations of auroral electron spectra and the structure of auroral arcs.
|
0.958 |
1986 — 1990 |
Lin, Anthony Dawson, John (co-PI) [⬀] |
N/AActivity Code Description: No activity code was retrieved: click on the grant title for more information |
Computer Simulations of Radiation Generation From Relativis-Tic Electron Beams @ University of California-Los Angeles
The PI's propose to use improved relativistic electromagnetic particle codes as well as existing codes developed under their previous NSF grant (ECS-8219105) to address crucial issues concerning the generation of coherent radiation from relativistic electron beams. The simulation studies will be carried out in the microwave range and will include the free-electron laser, electron cyclotron maser, and Cherenkov maser. The research will investigate: the effects of ac and dc space charge fields on the gain, resonant condition and nonlinear efficiency of various high current free electron devices; the transverse mode competition in various free electron devices; the effectiveness of using a background plasma for beam dc space charge and current neutralization and the feasibility of using the interaction between relativistic electron beams and plasma filled waveguides to build coherent radiation sources; and the efficiency of a Cherenkov maser in a planar dielectric waveguide and a high-harmonic gyrotron using axis-encircling large electron orbits.
|
0.958 |
1988 — 1991 |
Dawson, John H [⬀] |
R01Activity Code Description: To support a discrete, specified, circumscribed project to be performed by the named investigator(s) in an area representing his or her specific interest and competencies. |
Chemical Models For Biological Electron Transfer @ University of South Carolina At Columbia
A number of biological processes depend critically upon electron transfer: oxidative phosphorylation, photosynthesis and the redox reactions of metalloenzymes to name just a few. If a basic understanding of such systems is to be achieved, their remarkable efficiency and selectivity must be explained. The distance of separation between redox sites and the driving force of the electron transfer reaction are thought to play crucial roles in controlling the rate of electron transfer. This proposal presents an extensive program of research designed to probe the effects of distance and driving force on the rates of thermal electron transfer between metals. To that end, a series of binuclear metal complexes will be prepared where the bridging ligands are saturated structures that rigidly hold the two metals a defined distance apart and where that distance can be systematically varied. In addition, the complexes have been designed so that the difference in reduction potentials of the two metals is known and can also be changed. Two general approaches have been presented. (A) In the first system, a series of Ru2 and Os2 bipyridyl complexes will be used to indirectly probe the mechanism of electron transfer by studying the physical properties (intervalence charge transfer transitions, comproportionation constant, and electronic delocalization and coupling) of the mixed valence (M---M+) states. (B) In the second approach, a series of Ru---Os bipyridyl complexes will be employed to directly measure rates of electron transfer between the metals so as to probe the effect of distance on the rate at a fixed potential. In addition, by changing the substituents on the bipyridyl ligands bound to each metal, the reduction potentials of the two metal sites will be varied in order to study (1) the effect of redox asymmetry on the properties of the mixed valence states and (2) to determine the rate of electron transfer as a function of driving force at constant distance. There have been numerous theoretical treatments of the effects of distance and driving force on the physical properties of mixed valence complexes and on the rate of electron transfer. The data obtained through this overall approach will provide several stringent experimental tests of these theories. It is only through the systematic investigation of structurally defined binuclear metal complexes bridged by non- conjugated ligands that an accurate picture will emerge of the role played by distance and driving force in determining the properties of mixed valence states and the rate of electron transfer between metals.
|
0.916 |
1988 |
Dawson, John H [⬀] |
S10Activity Code Description: To make available to institutions with a high concentration of NIH extramural research awards, research instruments which will be used on a shared basis. |
Purchase of a Circular Dichroism Spectrophotometer @ University of South Carolina At Columbia
Funds are requested for the purchase of a state of the art circular dichroism spectrophotometer with accessories for stopped flow and low temperature experiments and with a 15 kilogauss electromagnet to enable magnetic circular dichroism to be carried out. The new instrument will replace a thirteen year old model that has become obsolete and unreliable. The new instrument is twenty times more sensitive than the old model and is configured for simultaneous measurement of UV-visible absorption and circular dichroism spectra. The new instrument will also be equipped to make measurements from 175 to 1050 nm, a much expanded spectral window from that currently available. The specific areas of research of the primary users will focus on the use of the new instrument for the following purposes: (a) the continued development of magnetic circular dichroism spectroscopy as a probe of heme iron coordination structure and the initial examination of the use of this technique to study chlorin iron systems, (b) the application of circular dichroism spectroscopy to investigate and quantify the allosteric interconversion of the R and T states of chemically modified hemoglobins, (c) the use of stopped flow circular dichroism spectroscopy to study the mechanism of action of native thymidylate synthase and the use of circular dichroism spectroscopy to characterize selected mutant enzymes generated by site directed mutagenesis, and (d) the investigation of the circular dichroism properties of selenium containing biomolecules, particularly seleno-sulfides and di-selenides, in order to evaluate the potential utility of the method as a probe of the structure of selenobiomolecules.
|
0.916 |
1989 — 1990 |
Dawson, John |
N/AActivity Code Description: No activity code was retrieved: click on the grant title for more information |
Symposium On: the Chemistry of Metal Ions in Biological Andbiomimetic Systems; Honolulu, Hawaii, December 17-22, 1989 @ American Chemical Society (Acs)
A Symposium on "The Chemistry of Metal Ions in Biological and Biomimetic Systems" will be held on December 17, 1989 at the International Congress of Pacific Basin Societies. This conference will bring together investigators concerned with (1) Metalloenzymes: active site structures and properties; (2) Biomimetic metal complexes: models for structural and catalytic properties; (3) Metal-biomolecule interactions; and (4) Molecular targets of metals in biological systems. It is expected that a synergistic interaction between the conferees will result.
|
0.919 |
1990 — 1992 |
Kennel, Charles (co-PI) [⬀] Pritchett, Philip Dawson, John [⬀] Wu, Cheng-Chin |
N/AActivity Code Description: No activity code was retrieved: click on the grant title for more information |
Numerical Studies of Magnetospheric Dynamics & Related Spaceplasma Processes @ University of California-Los Angeles
Numerical simulations are important tools for the study of space plasma physics. This grant is for continued research support to study the properties of shock waves and discontinuities in dissipative MHD and kinetic theory, the dynamics of the magnetosphere, and collisionless tearing instability in the magnetotail. Hybrid and implicit particle simulations will be used to study the kinetic properties of intermediate shocks and the possible role of such structures in dayside reconnection in the Earth's magnetotail will be investigated using increasingly realistic models of the near Earth plasma sheet. The principal aim will be to understand how and when a new neutral line forms within the pre-existing closed field lines of the plasma sheet.
|
0.958 |
1992 — 1994 |
Lovell, Charles (co-PI) [⬀] Dawson, John [⬀] Odom, Jerome (co-PI) [⬀] Dunlap, R. Bruce (co-PI) [⬀] Wuthier, Roy (co-PI) [⬀] |
N/AActivity Code Description: No activity code was retrieved: click on the grant title for more information |
Establishment of a Fermentation Facility @ University of South Carolina At Columbia
Funds are requested for instrumentation necessary to establish the fermentation protein of a complete Cell Culture Facility in the Institute for Biological Research and Technology at the University of South Carolina. This facility will replace an unusable 28 L fermenter, and will provide a wide range of fermentation services to the University community. The User Group includes faculty from the Department of Chemistry and Biological Sciences, as well as the College of Pharmacy and School of Medicine. The scope of projects to be supported by this instrumentation includes: (1) studies on the structure and function of hemeiron oxygenase enzymes; (2) mechanistic studies on thymidylate synthase; (3) studies on mammalian gene expression; (4) work on thymidylate synthase and fluoropyrimidine resistance; (5) structure function studies on matrix vesicle annexins; (6) using selenium as a probe of structure/function of biomacromolecules; (7) examining physiology, ecology, and evolution of bacterial functional group; (8) studies of the genetics of coal solubiolization; (9) mechanism of gene regulation in Caulobacter; (10) structural studies of rat spermatid transition protein 2; (11) examining the interaction of antitumor agents azinomycin A and B with DNA; (12) mechanistic studies of enolase; (13) cell division gene products of Bacillus subtilis; (14) role of human papillomaviruses in the transformation of human cells; (15) formation and role of pseudouridine in mRNA splicing cofactors; (16) preclinical evaluation of a human recombinant alph B/D hybrid interferon in therapy of hepatitis and papillomavirus infections; and (17) integrins and their interaction with the extracellular matrix.
|
0.958 |
1995 — 1996 |
Dawson, John |
N/AActivity Code Description: No activity code was retrieved: click on the grant title for more information |
Symposium On Metal Ions in Biology and Medicine: Natural and Synthetic Approaches to Be Held in Honolulu, Hawaii 17-22 December 1995. @ American Chemical Society (Acs)
; R o o t E n t r y F Ko4 4 C o m p O b j b W o r d D o c u m e n t O b j e c t P o o l Ko4 4 Ko4 4 ( ! " # $ % & ' ) * + , - . / 0 1 2 3 4 5 6 7 8 9 : ; < = > ? @ A B C D E F G H I J F Microsoft Word 6.0 Document MSWordDoc Word.Document.6 ; e = e J J n n n n n n n D 1 # & u T ; D n D n n n n n n n n 5 9511927 Dawson This symposium Metal Ions in Biology and Medicine: Natural and Synthetic Approaches will be held in Honolulu, Hawaii, December 17-22, 1995. It will bring to the attention of the chemical community new advances in the area of the structural and catalytic properties of metalloenzymes, the use of biomimetic metal complexes to model the structural and catalytic properties of metalloenzymes, and to introduce the emerging research areas of metal-nucleic acid interactions and therapeutic uses of metal complexes. %%% Metal ions play an essential and yet imperfectly understood role in biological catalysis and participate in a large number of transformations within cells. This meeting brings together biochemists, biophysicists, and inorganic chemists who actively study the role of metal ions in biology and medicine. *** ; Oh +' 0 $ H l D h R:\WWUSER\TE MPLATE\NORMAL.DOT S u m m a r y I n f o r m a t i o n ( 9511927 marcia steinberg marcia steinberg @ I y 4 @ @ {\! 4 @ Microsoft Word 6.0 2 ; E F J U F J ! ! ! ! K @ Normal a b c " A@ " Default Paragraph Font J J J J 5 marcia steinberg!\\CLM11\MCBPUB\BIOCHEM\DAWSON.ABS @HP DeskJet Printers LPT1: HPDSKJET HP DeskJet D L f , , " W d }w;W } d " W HP DeskJet D L f , , " W d }w;W } d " W I I I F 1 Times New Roman Symbol & Arial " h .3 EE3 E $ ; 9511927 marcia steinberg marcia steinberg ; ;
|
0.919 |
1997 — 2000 |
Dawson, John [⬀] |
N/AActivity Code Description: No activity code was retrieved: click on the grant title for more information |
Collective Absorption Processes of Neutrinos in Supernovae @ University of California-Los Angeles
AST- 9713234 ABSTRACT - J. M. Dawson COLLECTIVE ABSORPTION PROCESSES OF NEUTRINOS IN SUPERNOVAE A program to investigate the influence of collective interactions of the intense neutrino flux from the core of a supernova with the plasma of it's surrounding stellar envelope will be carried out. The mechanism is similar to the Forward Raman Instability that occurs when intense light interacts with plasma by generating electron plasma waves. In the neutrino case, the instability is much weaker due to the weakness of the neutrino electron interaction. Recent work at UCLA has shown that because of the extreme conditions that exist in a supernova, the forward Raman instability takes place. In the photon plasma case this instability increases the interaction with the plasma by many orders of magnitude. By analogy, large enhancements of the neutrino plasma coupling can be expected. The neutrinos carry away most of the energy of the supernova (100 times the light output). Models of supernova explosions have run into problems explaining how the supernova explodes if so much energy is carried off by the neutrinos and additional energy must be expended in dissociating iron and other heavy nuclei. Explosions can be made to occur if a few percent of the neutrino energy can be deposited in the stellar envelope. The forward Raman instability appear to be strong enough to do this and thus to influence the dynamics of the supernova. Techniques for computing the transport of the neutrinos through the stellar plasma and the resulting energy transfer will be developed. This will involve two quasi-linear equations, one for neutrinos and one for electrons, plus an equation for the evolution of plasma waves. The quasi-linear equation for the neutrinos describe the evolution of the neutrino spectrum due to their interaction with the plasma waves. The plasma wave equation computes the spectrum of plasma waves produced by the neutrinos and includes damping by electrons and the r esultant flow of energy from neutrinos to electrons. The quasi linear equation for the electrons describes the evolution of the electron distribution function; this is primarily a heating. When the electrons become hot enough (~ 500Kev) the Forward Raman Instability becomes the Forward Stimulated Compton Instability because the waves become heavily Landau damped. It is expected that the Forward Stimulated Compton Instability will be much weaker and to effectively turn off. Computer software codes to solve these coupled equations will be written and then used to explore the neutrino energy deposited in the electrons and the electron temperatures reached as a function of position in the star. The effects of the interaction on the neutrino energy distribution will be calculated to explore possible signatures of the process that might be detectable.
|
0.958 |
1997 — 2000 |
Dawson, John H [⬀] |
R01Activity Code Description: To support a discrete, specified, circumscribed project to be performed by the named investigator(s) in an area representing his or her specific interest and competencies. |
Cytochrome P450 Active Oxygen Structure and Mechanisms @ University of South Carolina At Columbia
DESCRIPTION: Understanding dioxygen activation by the cytochrome P450 mono-oxygenases requires knowledge of structure at the molecular level. Serving both beneficial and harmful roles in membrane detoxification and carcinogen activation respectively, the cytochromes P450 have been intensively studied. Pseudomonas putida P450-CAM is the best understood P450 in terms of structure and function. The structures of four P450 reaction states (two ferric, deoxyferrous and oxyferrous) have been established. Following second electron transfer, ferric -peroxide and oxo-ferryl adducts have been proposed as intermediates, the latter as the active oxygen catalyst. To observe and spectroscopically characterize such species for the first time, two approaches will be pursued: the use of "slow substrates" blocked at the normal reaction site to impede oxygen transfer and the use of rapid, photointitiated electron transfer to speed electron delivery. This two prong approach will enhance the likelihood of observing the elusive intermediate. In parallel, X-ray absorption spectroscopy will be used to structurally characterize oxo-ferryl states of chloroperoxidase (CPO) and ferric and ferrous states of nitric oxide synthase (NOS). CPO is the only heme protein clearly established to form thiolate-ligated oxo-ferryl intermediates such as that proposed for P450. Like P450, NOS is a thiolate-ligated heme enzyme. Determination of accurate Fe-S(Cys), Fe-N(porph) and Fe=O bond lengths in the CPO and NOS systems will provide structural information directly applicable to the P450 systems also under study. In addition, will be developed the camphor hydroxylating P450-CAM as a versatile enzyme-based model system for mechanistic studies of important P450 reaction types that are difficult to study due to the insolubility and/or complexity of the natural systems. Dr. Dawson will synthesize appropriately functionalized camphor analogues to use as substrates to customize the model system for each reaction type. The three reactions to be examined are: the C-C bond cleaving deformylation reaction, a reaction of great importance in steroid biosynthesis; the second step in the synthesis of the essential biomolecule nitric oxide (NO) in which NO is produced from arginine by nitric oxide synthase; and the P450-catalyzed conversion of nitosamines to NO dealkylated amines, formaldehyde and carinogenic diazoalkanes. The interplay of structure and mechanism is a common theme in all of the proposed work.
|
0.916 |
2000 — 2003 |
Dawson, John H [⬀] |
R01Activity Code Description: To support a discrete, specified, circumscribed project to be performed by the named investigator(s) in an area representing his or her specific interest and competencies. |
Spectroscopic and Mechanistic Studies of Heme Enzymes @ University of South Carolina At Columbia
DESCRIPTION: (adapted from applicant's abstract) This proposal seeks support for a program of spectroscopic and mechanistic studies of heme iron enzymes. Three important goals will be pursued. First, a fundamental aspect of protein structure will be tested: the Fe-S bond is retained in all oxidation states of cytochrome P450 and chloroperoxidase but only in ferric states of thiolate-ligated myoglobin (Mb) and cytochrome c peroxidase (CCP) mutants. The factors that lead to loss of thiolate ligation may be the same as in the active sites of the heme proteins that naturally lose thiolate ligation upon reduction. Guided by molecular modeling, Mb and CCP double/triple thiolate-ligated mutants will be prepared with H-bond donor amino acids positioned to stabilize the thiolate ligand toward reduction and oxoferryl formation. Formation of thiolate-ligated oxoferryl adducts would provide simple models for these important states. Second, use of UV-visible/near-IR magnetic circular dichroism (MCD) spectroscopy will be extended for axial ligand identification in heme and chlorin iron proteins. Heme enzymes are ubiquitous biomolecules; the function of each is significantly influenced by its axial ligands. Axial ligand identification in a new heme protein is always one of the first lines of study. MCD spectroscopy has already found great application for this purpose, but there is the potential to significantly extend its utility. Toward this end, a large number of axial ligand adducts will be prepared that involve ligand combinations not previously scrutinized by MCD. Next, MCD will be used to address key coordination structure issues for cystathione beta synthase, heme oxygenase, soluble guanylyl cyclase and iron chlorin-containing systems. The third goal is to study the mechanism of molecular oxygen activation by nitric oxide synthase (NOS) and P450. Oxyferrous NOS, stabilized at low temperatures, will be used for the first time as the starting point to address specific mechanistic questions. With P450, the putative peroxyferric intermediate reported with the D251N mutant will be characterized. Finally, spectroscopic experiments on oxyferrous states of thiolate-ligated heme proteins and their one-electron reduced products will significantly increase our knowledge of these important, but poorly understood heme states.
|
0.916 |
2001 — 2004 |
Decyk, Viktor Dawson, John (co-PI) [⬀] |
N/AActivity Code Description: No activity code was retrieved: click on the grant title for more information |
Numerical Investigation of Plasma Quantum Effects in Stellar Interiors @ University of California-Los Angeles
It is intended to study quantum effects in basic plasma processes (as occur in stellar interiors), and their consequences for plasma reaction rates and equations of state, with applications in stellar evolution (including the solar neutrino problem) and in the early universe (its energy density). The studies will utilize the novel multiparticle quantum code recently developed at UCLA, which is designed to handle hundreds of quantum particles.
|
0.958 |
2006 — 2009 |
Dawson, John H [⬀] |
R01Activity Code Description: To support a discrete, specified, circumscribed project to be performed by the named investigator(s) in an area representing his or her specific interest and competencies. |
Reactivity of Transient Cyt P450 Oxygen Intermediates @ University of South Carolina At Columbia
[unreadable] DESCRIPTION (provided by applicant): This proposal seeks support for investigations into the generation, characterization and, most importantly, reactivity of the 4 least well-understood cytochrome P450 (and related enzyme) transient intermediates - those involving oxygen: oxy-ferrous, peroxo-ferric, hydroperoxo-ferric, and oxo-iron(IV) [compound I, Cpd I, oxo-iron(IV)porph+]. 2 similar oxo species, compounds II and ES, will also be examined. 3 specific aims will be pursued. First (1), rapid kinetics methods will explore the role of hydrogen bonding in formation of a newly-observed "perturbed" oxy catalytic species by use of mutants with altered proximal and distal hydrogen bonding properties. Parallel studies of oxy NO synthase will use modified tetrahydrobiopterins to probe electron transfer. Second (2), the mechanism whereby peroxo and hydroperoxo P450 may serve as alternate oxidants will be tested using T252A P450-CAM, a mutant that forms those species but almost none of the primary oxidant, Cpd I. One-electron cryoreduction of oxy P450-CAM provides another way to study the peroxo and hydroperoxo states; solvent and substrate isotope effects on the annealing of the hydroperoxo state will reveal important mechanistic information about its reactivity. Both Aim 2 approaches will further test the "two oxidant" hypothesis of P450 reactivity. The third goal (3) is to characterize the properties and reactivities of transient oxo Cpd I (and related) intermediates. Having optimized conditions for P450-CAM Cpd I formation, we will use rapid freeze-quench methods to characterize it spectroscopically. This will establish its electronic properties, and help explain its reactivity. Double-mix stopped-flow experiments will examine Cpd I reactivity and clarify key mechanistic aspects of O atom transfer by peroxidases and P450. With P450-CAM, this will include the first direct reactions of Cpd I with substrates and determination of the intermolecular isotope effect for hydroxylation - a crucial test of the well-accepted "oxygen rebound" mechanism of hydroxylation. The knowledge derived from this work will lead to a more complete understanding of how heme enzymes activate peroxide and dioxygen with important medical implications for human health and disease, especially as described below for P450,. With over 3700 genes, P450 cytochromes are among the most essential and ubiquitous enzymes known. In human health, 57 P450s are responsible for countless critical transformations in steroid, vitamin D, eicosanoid, as well as drug metabolism. In human disease, P450-aromatase is a target for breast cancer chemotherapy owing to its vital role in estrogen hormone biosynthesis and several P450s have been shown to be activators of procarcinogens such as polycyclic aromatic hydrocarbons and nitrosamines. Progress in comprehending the P450 mechanism will promote medical advances to address these health issues. [unreadable] [unreadable] [unreadable]
|
0.916 |
2008 — 2014 |
Dawson, John [⬀] Ely, Bert (co-PI) [⬀] Lebioda, Lukasz (co-PI) [⬀] |
N/AActivity Code Description: No activity code was retrieved: click on the grant title for more information |
Mechanistic and Structural Studies of Novel Heme-Containing Enzymes @ University South Carolina Research Foundation
Intellectual Merit. Heme-iron containing peroxidases are enzymes that catalyze organic substrate oxidation while reducing hydrogen peroxide to water. Two novel heme peroxidases isolated from marine sea worms, one able to incorporate halide ions such as chloride and bromide into aromatic molecules and the other able to remove them, will be studied. The haloperoxidase, Notomastus lobatus chloroperoxidase (NCPO), halogenates phenols and is unusual in requiring an organic flavin component. Amphitrite ornata dehaloperoxidase (DHP) dehalogenates halophenols. Surprisingly, the structure of DHP is that of a globin - the same protein fold found in hemo- and myoglobin (Mb). It is the first known enzymatic globin. The unique structural properties of these two peroxidases bring into question whether they utilize a new peroxidase mechanism. A four-prong hypothesis-driven experimental plan will be followed. First, rapid kinetics experiments will probe the mechanism of DHP and NCPO catalysis and directly determine whether the traditional or an alternative mechanism is employed. Second, the ability of DHP and NCPO to carry out standard peroxidase reactions will be extensively tested in order to advance our understanding of DHP and NCPO function. Third, designed DHP and Mb mutants will be prepared to probe the mechanistic role of specific amino acids near the DHP heme and explore factors in the heme/globin environment that enhance DHP function relative to Mb. Fourth, NCPO will be cloned, expressed and structurally characterized. Small NCPO crystals have been obtained. NCPO is a complex multi-subunit hemoflavoenzyme; the roles of its subunits are unknown. Such enzymes with peroxidase activity have not yet been reported. Studies of its structure and mechanism will provide new information about halogenation in higher organisms. Investigations of complex multi-subunit-containing systems, such as those proposed herein, are at the cutting edge of mechanistic enzymology. Overall, the two novel peroxidases challenge the current view of how peroxidases function. The research will probe how nature has redesigned small globin-fold proteins into peroxidases and thereby will extend the boundaries of our understanding of structure/function relations in such enzymes.
Broader Impacts. The research combines the diverse disciplines of chemistry, molecular genetics and evolution, structural biology, and spectroscopy, and promotes interaction among chemistry and biology faculty and students via regular meetings of the three research groups. Students, from high school to post-graduate, will be trained. Undergraduates will continue to make significant research contributions. The three PIs have strong records training underrepresented minorities recently including two African-American students. One of the PIs directs SCienceLab, an outreach program for middle/high school science teachers and students. A specific 'Enzyme-Catalyzed Toxic Cleanup' SCiLab designed around biological dehaloperoxidases will provide a daylong hands-on, inquiry-based lab experience and convey the excitement of interfacing biological, chemical and environmental research. The goal is to show students how biological catalysts might be used in bioremediation technology. Moreover, the research results will continue to be used teaching graduate enzymology, crystallography and metallobiochemistry courses. The fundamental chemical/biochemical progress achieved may lead to the development of applications in the broader areas of biotechnology and bioremediation and will impact related ecological and environmental research.
|
0.942 |
2011 — 2014 |
Shimizu, Linda (co-PI) [⬀] Dawson, John [⬀] Rassolov, Vitaly (co-PI) [⬀] Garashchuk, Sophya (co-PI) [⬀] Adams, Richard (co-PI) [⬀] |
N/AActivity Code Description: No activity code was retrieved: click on the grant title for more information |
Acquisition of a Computer Cluster For Wide Range Chemical Applications and Education @ University South Carolina Research Foundation
With this award from the Chemistry Research Instrumentation and Facilities: Multi-user (CRIF:MU) program, Professor John Dawson and colleagues Richard Adams, Sophya Garashchuk, Vitaly Rassolov and Linda Shimizu from University of South Carolina will acquire a computer cluster. The award will enhance research training and education at all levels, especially in areas of study such as (a) chemistry of transition metal cluster complexes, (b) effects of zero-point energy on reactivity of methane, (c) spin properties of aromatic radicals, (d) porous nanoreactors from macrocyclic urea, and (e) synthesis and characterization of new complex photoluminescent oxides.
A cluster of fast, modern computers is vital to serving the computing needs of active research departments. Such a "computer network" also serves as a development environment for new theoretical codes and algorithms, provides state-of-the-art graphics and visualization facilities, and supports research in state-of-the-art applications of parallel processing. The computing resource will permit research, research training, and research outreach opportunities the neighboring colleges such as Claflin University, USC Aiken, Newberry College, Allen University and Presbyterian College.
|
0.942 |