+publisher:"Georgia Tech" +contributor:("Roger Wartell")

Georgia Tech

1. Orwig, Susan D. Biophysical and structural characterization of proteins implicated in glaucoma and Gaucher disease.

Degree: PhD, Chemistry and Biochemistry, 2011, Georgia Tech

► The inherited form of primary open angle glaucoma, a disorder characterized by increased intraocular pressure and retina degeneration, is linked to mutations in the olfactomedin… (more)

▼ The inherited form of primary open angle glaucoma, a disorder characterized by increased intraocular pressure and retina degeneration, is linked to mutations in the olfactomedin (OLF) domain of the myocilin gene. Disease-causing myocilin variants accumulate within trabecular meshwork cells instead of being secreted to the trabecular extracellular matrix thought to regulate aqueous humor flow and control intraocular pressure. Like other diseases of protein misfolding, we hypothesize myocilin toxicity originates from defects in protein biophysical properties. In this thesis, the first preparative recombinant high-yield expression and purification system for the C-terminal OLF domain of myocilin (myoc-OLF) is described. To determine the relative stability of wild-type (WT) and mutant OLF domains, a fluorescence thermal stability assay was adapted to provide the first direct evidence that mutated OLF is folded but less thermally stable than WT. In addition, mutant myocilin can be stabilized by chemical chaperones. Together, this work provides the first quantitative demonstration of compromised stability among identified OLF variants and placing myocilin glaucoma in the context of other complex diseases of protein misfolding. Subsequent investigations into the biophysical properties of WT myoc-OLF provide insight into its structure and function. In particular, myoc-OLF is stable in the presence of glycosaminoglycans (GAGs), as well as over a wide pH range in buffers with functional groups reminiscent of such GAGs. Myoc-OLF contains significant â-sheet and â-turn secondary structure as revealed by circular dichroism analysis. At neutral pH, thermal melts indicate a highly cooperative transition with a melting temperature of ~55°C. A compact core structural domain of OLF was identified by limited proteolysis and consists of approximately residues 238-461, which retains the single disulfide bond and is as stable as the full myoc-OLF construct. This construct also is capable of generating 3D crystals for structure determination. This data, presented in Chapter 3, inform new testable hypotheses for interactions with specific trabecular extracellular matrix components. To gain further insight into the biological function of myoc-OLF, a facile fluorescence chemical stability assay was designed to identify possible ligands and drug candidates. In the assay described in Chapter 4, the target protein is initially destabilized with a chemical denaturant and is tested for re-stabilization upon the addition of small molecules. The assay requires no prior knowledge of the structure and/or function of the target protein, and it is amendable to high-throughput screening. Application of the assay using a library of 1,280 compounds revealed 14 possible ligands and drug candidates for myoc-OLF that may also generate insights into myoc-OLF function. Due to the high â-sheet content of monomeric myoc-OLF and presence of an aggregated species upon myoc-OLF purification, the ability of myoc-OLF to form amyloid fibrils was suspected and… Advisors/Committee Members: Dr. Raquel Lieberman (Committee Chair), Dr. A. (Yomi) Oyelere (Committee Member), Dr. Al Merril (Committee Member), Dr. Loren Williams (Committee Member), Dr. Nicholas Hud (Committee Member), Dr. Roger Wartell (Committee Member).

Subjects/Keywords: Open-angle glaucoma; Pharmacological chaperones; High-throughput drug screen; Amyloid fibrils; Gaucher disease; Myocilin; Glaucoma; Eye Diseases; Eye Diseases Genetic aspects; Intraocular pressure; Body fluids Pressure; Eye

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APA (6^th Edition):

Orwig, S. D. (2011). Biophysical and structural characterization of proteins implicated in glaucoma and Gaucher disease. (Doctoral Dissertation). Georgia Tech. Retrieved from http://hdl.handle.net/1853/45816

Chicago Manual of Style (16^th Edition):

Orwig, Susan D. “Biophysical and structural characterization of proteins implicated in glaucoma and Gaucher disease.” 2011. Doctoral Dissertation, Georgia Tech. Accessed January 15, 2021. http://hdl.handle.net/1853/45816.

MLA Handbook (7^th Edition):

Orwig, Susan D. “Biophysical and structural characterization of proteins implicated in glaucoma and Gaucher disease.” 2011. Web. 15 Jan 2021.

Vancouver:

Orwig SD. Biophysical and structural characterization of proteins implicated in glaucoma and Gaucher disease. [Internet] [Doctoral dissertation]. Georgia Tech; 2011. [cited 2021 Jan 15]. Available from: http://hdl.handle.net/1853/45816.

Council of Science Editors:

Orwig SD. Biophysical and structural characterization of proteins implicated in glaucoma and Gaucher disease. [Doctoral Dissertation]. Georgia Tech; 2011. Available from: http://hdl.handle.net/1853/45816

2. Boz, Mustafa Burak. Modeling and simulations of single stranded rna viruses.

Degree: PhD, Chemistry and Biochemistry, 2012, Georgia Tech

URL: http://hdl.handle.net/1853/44815

► The presented work is the application of recent methodologies on modeling and simulation of single stranded RNA viruses. We first present the methods of modeling… (more)

▼ The presented work is the application of recent methodologies on modeling and simulation of single stranded RNA viruses. We first present the methods of modeling RNA molecules using the coarse-grained modeling package, YUP. Coarse-grained models simplify complex structures such as viruses and let us study general behavior of the complex biological systems that otherwise cannot be studied with all-atom details. Second, we modeled the first all-atom T=3, icosahedral, single stranded RNA virus, Pariacoto virus (PaV). The x-ray structure of PaV shows only 35% of the total RNA genome and 88% of the capsid. We modeled both missing portions of RNA and protein. The final model of the PaV demonstrated that the positively charged protein N- terminus was located deep inside the RNA. We propose that the positively charged N- terminal tails make contact with the RNA genome and neutralize the negative charges in RNA and subsequently collapse the RNA/protein complex into an icosahedral virus. Third, we simulated T=1 empty capsids using a coarse-grained model of three capsid proteins as a wedge-shaped triangular capsid unit. We varied the edge angle and the potentials of the capsid units to perform empty capsid assembly simulations. The final model and the potential are further improved for the whole virus assembly simulations. Finally, we performed stability and assembly simulations of the whole virus using coarse-grained models. We tested various strengths of RNA-protein tail and capsid protein-capsid protein attractions in our stability simulations and narrowed our search for optimal potentials for assembly. The assembly simulations were carried out with two different protocols: co-transcriptional and post-transcriptional. The co-transcriptional assembly protocol mimics the assembly occurring during the replication of the new RNA. Proteins bind the partly transcribed RNA in this protocol. The post-transcriptional assembly protocol assumes that the RNA is completely transcribed in the absence of proteins. Proteins later bind to the fully transcribed RNA. We found that both protocols can assemble viruses, when the RNA structure is compact enough to yield a successful virus particle. The post-transcriptional protocol depends more on the compactness of the RNA structure compared to the co-transcriptional assembly protocol. Viruses can exploit both assembly protocols based on the location of RNA replication and the compactness of the final structure of the RNA. Advisors/Committee Members: Stephen C. Harvey (Committee Chair), Adegboyega Oyelere (Committee Member), Loren Williams (Committee Member), Rigoberto Hernandez (Committee Member), Roger Wartell (Committee Member).

Subjects/Keywords: Virus assembly; Coarse-grained models; RNA virus; RNA viruses; RNA; Nucleic acids

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APA (6^th Edition):

Boz, M. B. (2012). Modeling and simulations of single stranded rna viruses. (Doctoral Dissertation). Georgia Tech. Retrieved from http://hdl.handle.net/1853/44815

Chicago Manual of Style (16^th Edition):

Boz, Mustafa Burak. “Modeling and simulations of single stranded rna viruses.” 2012. Doctoral Dissertation, Georgia Tech. Accessed January 15, 2021. http://hdl.handle.net/1853/44815.

MLA Handbook (7^th Edition):

Boz, Mustafa Burak. “Modeling and simulations of single stranded rna viruses.” 2012. Web. 15 Jan 2021.

Vancouver:

Boz MB. Modeling and simulations of single stranded rna viruses. [Internet] [Doctoral dissertation]. Georgia Tech; 2012. [cited 2021 Jan 15]. Available from: http://hdl.handle.net/1853/44815.

Council of Science Editors:

Boz MB. Modeling and simulations of single stranded rna viruses. [Doctoral Dissertation]. Georgia Tech; 2012. Available from: http://hdl.handle.net/1853/44815

Georgia Tech

3. Mills, Heath Jordan. Microbial diversity in sediments and gas hydrates associated with cold seeps in the Gulf of Mexico.

Degree: PhD, Biology, 2004, Georgia Tech

URL: http://hdl.handle.net/1853/5022

► A molecular phylogenetic approach was used to characterize the composition of microbial communities from two gas hydrate sedimentary systems in the Gulf of Mexico. Nucleic… (more)

▼ A molecular phylogenetic approach was used to characterize the composition of microbial communities from two gas hydrate sedimentary systems in the Gulf of Mexico. Nucleic acids were extracted from three distinct locales on surface breaching gas hydrate mounds, i.e., sediment overlaying gas hydrate, sediment/hydrate interface and sediment-free hydrate, and from three sediment depths, i.e., 0-2, 6-8 and 10-12 cm, in Beggiatoa sp. mat-associated sediments located several meters from exposed gas hydrate. Samples were collected from a research submersible (water depth 550-575 m) during two research cruises aboard the R/V Seward Johnson I and II funded by the NSF Life in Extreme Environments program. The 16S rRNA gene and 16S rRNA were amplified using PCR and reverse transcription-PCR, respectively, from DNA and RNA extracted from the total microbial community. The primers targeted microorganisms at the domain-specific, i.e., Bacteria and Archaea, and group-specific, i.e., sulfate-reducing bacteria (SRB) and putative anaerobic methane-oxidizing (ANME) archaea, level. Sequence analysis of the Bacteria clones revealed that the microbial communities were primarily dominated by Deltaproteobacteria. Other Proteobacteria classes, including Epsilon- and Gammaproteobacteria, represented a large fraction of the total microbial community isolated from the sediment overlying hydrate sample and the metabolically active fraction of the 0-2 cm sediment depth sampled from the Beggiatoa sp. mat-associated sediments. Sequence analysis indicated the majority of the archaeal clones were most closely related to Methanosarcinales, Methanomicrobiales and distinct lineages within the ANME groups. Several novel lineages were identified including a fourth ANME-2 clade, i.e., ANME-2D, and three clades with no closely related previously sequenced 16S rRNA gene clones or isolates, i.e., Unclassified Bacteria groups 1 and 2 and Unclassified Euryarchaeota. These studies represent the first 16S rRNA gene and 16S rRNA phylogenetic-based description of microbial communities extant in sediment-free gas hydrate and in methane-rich hydrate-associated and Beggiatoa sp.-associated sediments from a hydrocarbon seep region in the Gulf of Mexico. Advisors/Committee Members: Patricia Sobecky (Committee Chair), Frank Loeffler (Committee Member), Joseph Montoya (Committee Member), Roger Wartell (Committee Member), Thomas DiChristina (Committee Member).

Subjects/Keywords: Microbial diversity; 16S; Gulf of Mexico; Cold seep; Geochemistry Mexico, Gulf of; Microbial ecology

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APA (6^th Edition):

Mills, H. J. (2004). Microbial diversity in sediments and gas hydrates associated with cold seeps in the Gulf of Mexico. (Doctoral Dissertation). Georgia Tech. Retrieved from http://hdl.handle.net/1853/5022

Chicago Manual of Style (16^th Edition):

Mills, Heath Jordan. “Microbial diversity in sediments and gas hydrates associated with cold seeps in the Gulf of Mexico.” 2004. Doctoral Dissertation, Georgia Tech. Accessed January 15, 2021. http://hdl.handle.net/1853/5022.

MLA Handbook (7^th Edition):

Mills, Heath Jordan. “Microbial diversity in sediments and gas hydrates associated with cold seeps in the Gulf of Mexico.” 2004. Web. 15 Jan 2021.

Vancouver:

Mills HJ. Microbial diversity in sediments and gas hydrates associated with cold seeps in the Gulf of Mexico. [Internet] [Doctoral dissertation]. Georgia Tech; 2004. [cited 2021 Jan 15]. Available from: http://hdl.handle.net/1853/5022.

Council of Science Editors:

Mills HJ. Microbial diversity in sediments and gas hydrates associated with cold seeps in the Gulf of Mexico. [Doctoral Dissertation]. Georgia Tech; 2004. Available from: http://hdl.handle.net/1853/5022

Georgia Tech

4. Hazen, Tracy Heather. Genetic elements and molecular mechanisms driving the evolution of the pathogenic marine bacterium Vibrio parahaemolyticus.

Degree: PhD, Biology, 2009, Georgia Tech

URL: http://hdl.handle.net/1853/29611

► Vibrio parahaemolyticus is an opportunistic human pathogen that occurs naturally in a non-pathogenic form in coastal estuarine and marine environments worldwide. Following the acquisition of… (more)

▼ Vibrio parahaemolyticus is an opportunistic human pathogen that occurs naturally in a non-pathogenic form in coastal estuarine and marine environments worldwide. Following the acquisition of virulence-associated genes, V. parahaemolyticus has emerged as a significant pathogen causing seafood-borne illnesses. The mechanisms and conditions that promote the emergence of disease causing V. parahaemolyticus strains are not well understood. In addition, V. parahaemolyticus clinical strains isolated from disease-associated samples and environmental strains from sediment, water, and marine organisms have been identified with considerable diversity; however, the evolutionary relationships of disease-causing strains and environmental strains are not known. In the following research, the evolutionary relationships of V. parahaemolyticus clinical and environmental strains are examined. In addition, the contribution of genetic elements and molecular mechanisms such as deficiency of DNA repair to the evolution of V. parahaemolyticus clinical and environmental strains is shown. Molecular analysis of the evolutionary relationships of V. parahaemolyticus clinical and environmental strains demonstrated separate lineages of pathogenic and non-pathogenic strains with the exception of several environmental strains that may represent a reservoir of disease-causing strains in the environment. Sequence characterization of plasmids isolated from diverse environmental Vibrios indicated a role of plasmids in strain evolution by horizontal transfer of housekeeping genes. In addition, analysis of plasmids from V. parahaemolyticus clinical and environmental strains indicated the existence of a plasmid family distributed among V. parahaemolyticus, V. campbellii, and V. harveyi environmental strains. Sequence characterization of a plasmid of this family from a V. parahaemolyticus environmental strain indicated the contribution of these plasmids to the emergence of the clonal pandemic strains. Investigation of the role of molecular mechanisms to the evolution of V. parahaemolyticus strains showed that inactivation of the DNA repair pathway methyl-directed mismatch repair (MMR) increased the accumulation of spontaneous mutations leading to increased nucleotide diversity in select genes. The research findings in the following chapters demonstrate a considerable contribution of genetic elements and molecular mechanisms to the evolution of genetic and phenotypic diversity. Advisors/Committee Members: Patricia Sobecky (Committee Chair), Eric Stabb (Committee Member), Jim Spain (Committee Member), Roger Wartell (Committee Member), Thomas DiChristina (Committee Member).

Subjects/Keywords: Plasmid; Phage; MLST; Evolution; Vibrio parahaemolyticus; HGT; Horizontal gene transfer; Population; Mismatch repair; MALDI-TOF MS; Pathogenic bacteria; Molecular evolution; Genetic transformation; Bacterial transformation

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APA (6^th Edition):

Hazen, T. H. (2009). Genetic elements and molecular mechanisms driving the evolution of the pathogenic marine bacterium Vibrio parahaemolyticus. (Doctoral Dissertation). Georgia Tech. Retrieved from http://hdl.handle.net/1853/29611

Chicago Manual of Style (16^th Edition):

Hazen, Tracy Heather. “Genetic elements and molecular mechanisms driving the evolution of the pathogenic marine bacterium Vibrio parahaemolyticus.” 2009. Doctoral Dissertation, Georgia Tech. Accessed January 15, 2021. http://hdl.handle.net/1853/29611.

MLA Handbook (7^th Edition):

Hazen, Tracy Heather. “Genetic elements and molecular mechanisms driving the evolution of the pathogenic marine bacterium Vibrio parahaemolyticus.” 2009. Web. 15 Jan 2021.

Vancouver:

Hazen TH. Genetic elements and molecular mechanisms driving the evolution of the pathogenic marine bacterium Vibrio parahaemolyticus. [Internet] [Doctoral dissertation]. Georgia Tech; 2009. [cited 2021 Jan 15]. Available from: http://hdl.handle.net/1853/29611.

Council of Science Editors:

Hazen TH. Genetic elements and molecular mechanisms driving the evolution of the pathogenic marine bacterium Vibrio parahaemolyticus. [Doctoral Dissertation]. Georgia Tech; 2009. Available from: http://hdl.handle.net/1853/29611

Georgia Tech

5. Dale, Jason Robert. Cytochrome c maturation and redox homeostasis in uranium-reducing bacterium Shewanella putrefaciens.

Degree: PhD, Biology, 2007, Georgia Tech

URL: http://hdl.handle.net/1853/19846

► Microbial metal reduction contributes to biogeochemical cycling, and reductive precipitation provides the basis for bioremediation strategies designed to immobilize radionuclide contaminants present in the subsurface.… (more)

▼ Microbial metal reduction contributes to biogeochemical cycling, and reductive precipitation provides the basis for bioremediation strategies designed to immobilize radionuclide contaminants present in the subsurface. Facultatively anaerobic ×-proteobacteria of the genus Shewanella are present in many aquatic and terrestrial environments and are capable of respiration on a wide range of compounds as terminal electron acceptor including transition metals, uranium and transuranics. S. putrefaciens is readily cultivated in the laboratory and a genetic system was recently developed to study U(VI) reduction in this organism. U(VI) reduction-deficient S. putrefaciens point mutant Urr14 (hereafter referred to as CCMB1) was found to retain the ability to respire several alternate electron acceptors. In the present study, CCMB1 was tested on a suite of electron acceptors and found to retain growth on electron acceptors with high reduction potential (E¡¬0) [O2, Fe(III)-citrate, Mn(IV), Mn(III)-pyrophosphate, NO3-] but was impaired for anaerobic growth on electron acceptors with low E¡¬0 [NO2-, U(VI), dimethyl sulfoxide, trimethylamine N-oxide, fumarate, ×-FeOOH, SO32-, S2O32-]. Genetic complementation and sequencing analysis revealed that CCMB1 contained a point mutation (H108Y) in a CcmB homolog, an ABC transporter permease subunit required for c-type cytochrome maturation in E. coli. The periplasmic space of CCMB1 contained low levels of cytochrome c and elevated levels of free thiol equivalents (-SH), an indication that redox homeostasis was disrupted. Anaerobic growth ability, but not cytochrome c maturation activity, was restored to CCMB1 by adding exogenous disulfide bond-containing compounds (e.g., cystine) to the growth medium. To test the possibility that CcmB transports heme from the cytoplasm to the periplasm in S. putrefaciens, H108 was replaced with alanine, leucine, methionine and lysine residues via site-directed mutagenesis. Anaerobic growth, cytochrome c biosynthesis or redox homeostasis was disrupted in each of the site-directed mutants except H108M. The results of this study demonstrate, for the first time, that S. putrefaciens requires CcmB to produce c-type cytochromes under U(VI)-reducing conditions and maintain redox homeostasis during growth on electron acceptors with low E¡¬0. The present study is the first to examine CcmB activity during growth on electron acceptors with widely-ranging E¡¬0, and the results suggest that cytochrome c or free heme maintains periplasmic redox poise during growth on electron acceptors with E¡¬0 < 0.36V such as in the subsurface engineered for rapid U(VI) reduction or anoxic environments dominated by sulfate-reducing bacteria. A mechanism for CcmB heme translocation across the S. putrefaciens cytoplasmic membrane via heme coordination by H108 is proposed. Advisors/Committee Members: Thomas J. DiChristina (Committee Chair), Frank E. Loeffler (Committee Member), John R. Kirby (Committee Member), Martial Taillefert (Committee Member), Roger Wartell (Committee Member).

Subjects/Keywords: Anaerobic respiration; Shewanella putrefaciens; Cytochrome c maturation; Uranium reduction; Bioremediation; Biogeochemical cycles; Bioremediation; Radioisotopes

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APA (6^th Edition):

Dale, J. R. (2007). Cytochrome c maturation and redox homeostasis in uranium-reducing bacterium Shewanella putrefaciens. (Doctoral Dissertation). Georgia Tech. Retrieved from http://hdl.handle.net/1853/19846

Chicago Manual of Style (16^th Edition):

Dale, Jason Robert. “Cytochrome c maturation and redox homeostasis in uranium-reducing bacterium Shewanella putrefaciens.” 2007. Doctoral Dissertation, Georgia Tech. Accessed January 15, 2021. http://hdl.handle.net/1853/19846.

MLA Handbook (7^th Edition):

Dale, Jason Robert. “Cytochrome c maturation and redox homeostasis in uranium-reducing bacterium Shewanella putrefaciens.” 2007. Web. 15 Jan 2021.

Vancouver:

Dale JR. Cytochrome c maturation and redox homeostasis in uranium-reducing bacterium Shewanella putrefaciens. [Internet] [Doctoral dissertation]. Georgia Tech; 2007. [cited 2021 Jan 15]. Available from: http://hdl.handle.net/1853/19846.

Council of Science Editors:

Dale JR. Cytochrome c maturation and redox homeostasis in uranium-reducing bacterium Shewanella putrefaciens. [Doctoral Dissertation]. Georgia Tech; 2007. Available from: http://hdl.handle.net/1853/19846

Georgia Tech

6. Gokhale, Kavita Chandan. Interactions between endogenous prions, chaperones and polyglutamine proteins in the yeast model.

Degree: PhD, Biology, 2005, Georgia Tech

URL: http://hdl.handle.net/1853/6856

► Poly-Q expanded exon 1 of huntingtin (Q103) fused to GFP is toxic to yeast cells containing endogenous yeast prions, [PIN+] ([RNQ+]) and/or [PSI+], which presumably… (more)

Subjects/Keywords: Chaperones; Glutamine; Molecular chaperones; Prions; Yeast

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APA (6^th Edition):

Gokhale, K. C. (2005). Interactions between endogenous prions, chaperones and polyglutamine proteins in the yeast model. (Doctoral Dissertation). Georgia Tech. Retrieved from http://hdl.handle.net/1853/6856

Chicago Manual of Style (16^th Edition):

Gokhale, Kavita Chandan. “Interactions between endogenous prions, chaperones and polyglutamine proteins in the yeast model.” 2005. Doctoral Dissertation, Georgia Tech. Accessed January 15, 2021. http://hdl.handle.net/1853/6856.

MLA Handbook (7^th Edition):

Gokhale, Kavita Chandan. “Interactions between endogenous prions, chaperones and polyglutamine proteins in the yeast model.” 2005. Web. 15 Jan 2021.

Vancouver:

Gokhale KC. Interactions between endogenous prions, chaperones and polyglutamine proteins in the yeast model. [Internet] [Doctoral dissertation]. Georgia Tech; 2005. [cited 2021 Jan 15]. Available from: http://hdl.handle.net/1853/6856.

Council of Science Editors:

Gokhale KC. Interactions between endogenous prions, chaperones and polyglutamine proteins in the yeast model. [Doctoral Dissertation]. Georgia Tech; 2005. Available from: http://hdl.handle.net/1853/6856

Georgia Tech

7. Roberts, Lezah Wilette. Effect of Netropsin on One-electron Oxidation of DNA.

Degree: PhD, Chemistry and Biochemistry, 2005, Georgia Tech

URL: http://hdl.handle.net/1853/7228

► One electron oxidation of DNA has been studied extensively over the years. When a charge is injected into a DNA duplex, it migrates through the… (more)

Subjects/Keywords: Photosensitizer; Charge transfer; Netropsin; TQ; DNA; Electron transfer; One-electron oxidation; Photosensitization, Biological; Charge transfer in biology; DNA Analysis; Oxidation, Physiological

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APA (6^th Edition):

Roberts, L. W. (2005). Effect of Netropsin on One-electron Oxidation of DNA. (Doctoral Dissertation). Georgia Tech. Retrieved from http://hdl.handle.net/1853/7228

Chicago Manual of Style (16^th Edition):

Roberts, Lezah Wilette. “Effect of Netropsin on One-electron Oxidation of DNA.” 2005. Doctoral Dissertation, Georgia Tech. Accessed January 15, 2021. http://hdl.handle.net/1853/7228.

MLA Handbook (7^th Edition):

Roberts, Lezah Wilette. “Effect of Netropsin on One-electron Oxidation of DNA.” 2005. Web. 15 Jan 2021.

Vancouver:

Roberts LW. Effect of Netropsin on One-electron Oxidation of DNA. [Internet] [Doctoral dissertation]. Georgia Tech; 2005. [cited 2021 Jan 15]. Available from: http://hdl.handle.net/1853/7228.

Council of Science Editors:

Roberts LW. Effect of Netropsin on One-electron Oxidation of DNA. [Doctoral Dissertation]. Georgia Tech; 2005. Available from: http://hdl.handle.net/1853/7228

Georgia Tech

8. Horowitz, Eric D. Intercalator-mediated assembly of nucleic acids.

Degree: PhD, Chemistry and Biochemistry, 2009, Georgia Tech

URL: http://hdl.handle.net/1853/33937

► The RNA World hypothesis suggests that RNA, or a proto-RNA, existed in an early form of life that had not yet developed the ability to… (more)

▼ The RNA World hypothesis suggests that RNA, or a proto-RNA, existed in an early form of life that had not yet developed the ability to synthesize protein enzymes. This hypothesis, by some interpretations, implies that nucleic acid polymers were the first polymers of life, and must have therefore spontaneously formed from simple molecular building blocks in the "prebiotic soup." Although prebiotic chemists have searched for decades for a process by which RNA can be made from plausible prebiotic reactions, numerous problems persist that stand in the way of a chemically-sound model for the spontaneous generation of an RNA World (e.g., strand-cyclization, heterogeneous backbones, non-selective ligation of activated nucleotides). The Molecular Midwife hypothesis, proposed by Hud and Anet in 2000, provides a possible solution to several problems associated with the assembly of the first nucleic acids. In this hypothesis, nucleic acid base pairs are assembled by small, planar molecules that resemble molecules which are known today to intercalate the base pairs of nucleic acid duplexes. Thus, the validity and merits of the Molecular Midwife hypothesis can be, to some extent, explored by studying the effects of intercalation on the non-covalent assembly of nucleic acids. In this thesis, I explore the role of the sugar-phosphate backbone in dictating the structure and thermodynamics of nucleic acid intercalation by using 2′,5′-linked RNA intercalation as a model system of non-natural nucleic acid intercalation. The solution structure of an intercalator-bound 2′,5′ RNA duplex reveals structural and thermodynamic aspects of intercalation that provide insight into the origin of the nearest-neighbor exclusion principle, a principle that is uniformly obeyed upon the intercalation of natural (i.e. 3′,5′-linked) RNA and DNA. I also demonstrate the ability of intercalator-mediated assembly to circumvent the strand-cyclization problem, a problem that otherwise greatly limits the polymerization of short oligonucleotides into long polymers. Together, the data presented in this thesis illustrate the important role that the nucleic acid backbone plays in governing the thermodynamics of intercalation, and provide support for the proposed role of intercalator-mediated assembly in the prebiotic formation of nucleic acids. Advisors/Committee Members: Nicholas V. Hud (Committee Chair), David Sherrill (Committee Member), Loren Williams (Committee Member), Roger Wartell (Committee Member), Steve Harvey (Committee Member).

Subjects/Keywords: RNA; Intercalation; DNA; Nucleic acids; Origin of life; Template-directed synthesis; Life Origin; Oligonucleotides; Proteins Synthesis; Proteins

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APA (6^th Edition):

Horowitz, E. D. (2009). Intercalator-mediated assembly of nucleic acids. (Doctoral Dissertation). Georgia Tech. Retrieved from http://hdl.handle.net/1853/33937

Chicago Manual of Style (16^th Edition):

Horowitz, Eric D. “Intercalator-mediated assembly of nucleic acids.” 2009. Doctoral Dissertation, Georgia Tech. Accessed January 15, 2021. http://hdl.handle.net/1853/33937.

MLA Handbook (7^th Edition):

Horowitz, Eric D. “Intercalator-mediated assembly of nucleic acids.” 2009. Web. 15 Jan 2021.

Vancouver:

Horowitz ED. Intercalator-mediated assembly of nucleic acids. [Internet] [Doctoral dissertation]. Georgia Tech; 2009. [cited 2021 Jan 15]. Available from: http://hdl.handle.net/1853/33937.

Council of Science Editors:

Horowitz ED. Intercalator-mediated assembly of nucleic acids. [Doctoral Dissertation]. Georgia Tech; 2009. Available from: http://hdl.handle.net/1853/33937

Georgia Tech

9. Watkins, Jason Derrick. X-ray structures of p22 c2 repressor-dna complexes: the mechansism of direct and indirect readout.

Degree: PhD, Chemistry and Biochemistry, 2008, Georgia Tech

URL: http://hdl.handle.net/1853/26709

► The P22 c2 repressor protein (P22R) binds to DNA sequence-specifically and helps direct the temperate lambdoid bacteriophage P22 to the lysogenic developmental pathway. To gain… (more)

Subjects/Keywords: P22 repressor; Direct readout; Indirect readout; Protein binding; DNA-protein interactions; Van der Waals forces

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APA (6^th Edition):

Watkins, J. D. (2008). X-ray structures of p22 c2 repressor-dna complexes: the mechansism of direct and indirect readout. (Doctoral Dissertation). Georgia Tech. Retrieved from http://hdl.handle.net/1853/26709

Chicago Manual of Style (16^th Edition):

Watkins, Jason Derrick. “X-ray structures of p22 c2 repressor-dna complexes: the mechansism of direct and indirect readout.” 2008. Doctoral Dissertation, Georgia Tech. Accessed January 15, 2021. http://hdl.handle.net/1853/26709.

MLA Handbook (7^th Edition):

Watkins, Jason Derrick. “X-ray structures of p22 c2 repressor-dna complexes: the mechansism of direct and indirect readout.” 2008. Web. 15 Jan 2021.

Vancouver:

Watkins JD. X-ray structures of p22 c2 repressor-dna complexes: the mechansism of direct and indirect readout. [Internet] [Doctoral dissertation]. Georgia Tech; 2008. [cited 2021 Jan 15]. Available from: http://hdl.handle.net/1853/26709.

Council of Science Editors:

Watkins JD. X-ray structures of p22 c2 repressor-dna complexes: the mechansism of direct and indirect readout. [Doctoral Dissertation]. Georgia Tech; 2008. Available from: http://hdl.handle.net/1853/26709

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