Chemistry Commons^™

Evaluation Of Dft Methods To Study Reactions Of Benzene With Oh Radical, Steve Scheiner

Chemistry and Biochemistry Faculty Publications

Several density functional theory” (DFT) methods are applied to two different reaction channels involving OH• + C6H6, and the results compared with high-level ab initio calculations. The OH• adds directly to one C atom in the first channel, first forming an encounter complex with the OH• poised above the aromatic plane. B3LYP, BH&HLYP, and MPW1K compute an accurate estimate of the overall exothermicity, whereas M05-2X, PBE0, and PBEPBE overestimate this quantity to some degree. With the exceptions of PBEPBE and PBE0, the other methods produce an acceptable barrier to addition. All approaches except BH&HLYP correctly predict an exothermic H• abstraction, …

Structural Polymorphism In Tau Filaments: An Implication For Neurodegenerative Diseases, Ayisha Siddiqua

Electronic Theses and Dissertations

Tau filaments are the pathological hallmark of >20 neurodegenerative diseases including Alzheimer's disease, Pick's disease, and progressive supranuclear palsy. In the adult human brain, six isoforms of tau are expressed that differ by presence or absence of the second of the four semiconserved repeats. As a consequence, half of the tau isoforms have three repeats (3R tau), whereas the other half has four repeats (4R tau).

Site-directed spin labeling of recombinant tau in conjunction with electron paramagnetic resonance spectroscopy was used to obtain structural insights into tau filaments. The studies showed that the filaments of 4R tau and 3R tau …

Β-Casein–Phospholipid Monolayers As Model Systems To Understand Lipid–Protein Interactions In The Milk Fat Globule Membrane, Sophie Gallier, Derek E. Gragson, Rafael Jiménez-Flores, David W. Everett

Chemistry and Biochemistry

Phospholipid–protein monolayer films were studied as model systems to mimic the structure of the native bovine milk fat globule membrane (MFGM) and to understand lipid–protein interactions at the surface of the globule. Phospholipids extracted from bovine raw milk, raw cream, processed milk and buttermilk powder were spread onto the air–water interface of a Langmuir trough, β-casein was then added to the sub-phase, and Langmuir–Blodgett films were studied by epifluorescence microscopy and atomic force microscopy. In all films, β-casein was responsible for clustering of the sphingomyelin- and cholesterol-rich microdomains into larger platforms. This suggests that the same phenomenon may happen at …

Contributions Of Various Noncovalent Bonds To The Interaction Between An Amide And S-Containing Molecules, U. Adhikari, Steve Scheiner

Chemistry and Biochemistry Faculty Publications

N-Methylacetamide, a model of the peptide unit in proteins, is allowed to interact with CH3SH, CH3SCH3, and CH3SSCH3 as models of S-containing amino acid residues. All of the minima are located on the ab initio potential energy surface of each heterodimer. Analysis of the forces holding each complex together identifies a variety of different attractive forces, including SH⋅⋅⋅O, NH⋅⋅⋅S, CH⋅⋅⋅O, CH⋅⋅⋅S, SH⋅⋅⋅π, and CH⋅⋅⋅π H-bonds. Other contributing noncovalent bonds involve charge transfer into σ* and π* antibonds. Whereas some of the H-bonds are strong enough that they represent the sole attractive force in several dimers, albeit not usually in the …

Linus Pauling: Scientist Of The 20th Century, Laura Ward

Natural Sciences Student Research Presentations

This poster describes the contributions scientist Linus Pauling made to the fields of chemistry and molecular biology, including his hybridization theory.

Development Of A ‘Clickable’ Non-Natural Nucleotide To Visualize The Replication Of Non-Instructional Dna Lesions, Edward A. Motea, Irene Lee, Anthony J. Berdis

Chemistry Faculty Publications

The misreplication of damaged DNA is an important biological process that produces numerous adverse effects on human health. This report describes the synthesis and characterization of a non-natural nucleotide, designated 3-ethynyl-5-nitroindolyl-2′-deoxyriboside triphosphate (3-Eth-5-NITP), as a novel chemical reagent that can probe and quantify the misreplication of damaged DNA. We demonstrate that this non-natural nucleotide is efficiently inserted opposite an abasic site, a commonly formed and potentially mutagenic non-instructional DNA lesion. The strategic placement of the ethynyl moiety allows the incorporated nucleoside triphosphate to be selectively tagged with an azide-containing fluorophore using ‘click’ chemistry. This reaction provides a facile way to …

The Structural Requirements Of Histone Deacetylase (Hdac) Inhibitors: Suberoylanilide Hydroxamic Acid (Saha) Analogues Modified At C3, C6, And C7 Positions Enhance Selectivity, Sun Ea Choi

Wayne State University Dissertations

Histone deacetylase (HDAC) proteins are targets for drug design towards the treatment of cancers since overexpression of HDAC is linked to cancer. Several HDAC inhibitors, including the FDA approved drug suberoylanilide hydroxamic acid (SAHA, Vorinostat), have cleared clinical trials and emerged as anti-cancer drugs. However, SAHA inhibits all of the 11 metal ion-dependent HDAC proteins. Therefore, we synthesized several libraries of small molecule HDAC inhibitors based on SAHA to help understand the structural requirements of inhibitory potency and isoform selectivity.

In previous work, SAHA analogues functionalized at the C2 position (C2-SAHA analogues) near the metal binding hydroxamic acid displayed decreased …

Genetic And Biochemical Studies Of Human Apobec Family Of Proteins, Priyanga Wijesinghe

Wayne State University Dissertations

The AID/APOBEC family of proteins in higher vertebrates converts cytosines in DNA or RNA into uracil. These proteins have essential roles in either innate immunity or adaptive immunity. Recently, AID has also been implicated in DNA demethylation in the context of early embryogenesis in mammals. This is partly based on the reported ability of AID to deaminate 5-methyl cytosine to thymine (5mC to T). I reexamined this proposed new role of AID (5mC deamination) with two members of the APOBEC family in a novel Escherichia coli based genetic system. My results confirmed that while all three enzymes are strong cytosine …

Development Of A Cargo Delivery System And Inhibition Studies Focused On Clostridium Difficile Toxin A, Stephanie Marie Kern

Wayne State University Dissertations

Virulence factors of pathogenic bacteria are to be blamed for life-threatening infections such as diphtheria, anthrax, botulism, and tentanus. In the case of enzymatic exotoxins, disease arises from cytotoxic proteins, and cytotoxicity is acheived only after cell entry. This intrinsic mechanism for cell entry is intriguing from research and medical views. Along with a review on existing cargo delivery systems utilizing protein toxins and the usefulness of such a system, here is described the first reported Clostridium difficile toxin A fusion protein, luciferase-TcdA, and evidence of the successful transport of an active enzyme, luciferase, into the cytosol of vero cells. …

Effects Of Carbon Chain Substituent On The P∙∙∙N Noncovalent Bond, U. Adhikari, Steve Scheiner

Chemistry and Biochemistry Faculty Publications

The effects of carbon chains placed on the electron-accepting P atom of a P⋯N bond are examined via ab initio calculations. Saturated alkyl groups have a mild weakening effect, regardless of chain length. In contrast, incorporation of double bonds into the chain strengthens the interaction, Ctriple bond; length of mdashC triple bonds even more so. These effects are only slightly enhanced by additional conjugated double bonds or an aromatic ring. Placing F atoms onto the carbon chains strengthens the P⋯N bond, but only by a small amount, which wanes as the F atom is displaced further from the P along …

Removal Of Uracil By Uracil Dna Glycosylase Limits Pemetrexed Cytotoxicity: Overriding The Limit With Methoxyamine To Inhibit Base Excision Repair, A. D. Bulgar, L. D. Weeks, Y. Miao, S. Yang, Yan Xu, C. Guo, S. Markowitz, N. Oleinick, S. L. Gerson, Lili Liu

Chemistry Faculty Publications

Uracil DNA glycosylase (UDG) specifically removes uracil bases from DNA, and its repair activity determines the sensitivity of the cell to anticancer agents that are capable of introducing uracil into DNA. In the present study, the participation of UDG in the response to pemetrexed-induced incorporation of uracil into DNA was studied using isogenic human tumor cell lines with or without UDG (UDG+/+/UDG−/−). UDG−/− cells were very sensitive to pemetrexed. Cell killing by pemetrexed was associated with genomic uracil accumulation, stalled DNA replication, and catastrophic DNA strand breaks. By contrast, UDG+/+ cells were >10 times more resistant to pemetrexed due to …

Exploring Conformational Variability Of An Rna Domain In The Ribosome: From Structure And Function To Potential Antibiotic Targeting, Yogo Sakakibara

Wayne State University Dissertations

RNA in nature is modified at many specific sites to order to gain extra functions or to expand the genetic code. One of such RNAs is ribosomal RNA (rRNA), which contains several modified bases, particularly around the functionally significant sites. We have focused on understanding the influences of modified base on RNA structure and function by employing helix 69 (H69), which is a good region to evaluate the roles of modified bases since it contains three pseudouridines in the loop region and exists at the core of the ribosome.

Previous model studies using small hairpin H69 showed the conformational differences …

Development Of Mass Spectrometric Methods For The Analysis Of Serotonin And Related Compounds In Biological Matrices, Merisa Moriarty

Theses

Serotonin is a major neurotransmitter in the brain and affects various functions both in the brain and in the rest of the body. It has been linked to depression, migraines, and aggression, as well as many psychiatric disorders including schizophrenia, dementia and anorexia nervosa. It also has been associated with conditions like Alzheimer’s disease along with other neurotransmitters such as dopamine.

The aim of this research project is to develop various mass spectrometric methods for the analysis of serotonin, dopamine and similar indoles in both urine and serum matrices. This thesis provides extensive reviews detailing a general overview of serotonin …

Drug Resistance Mechanisms And Drug Design Strategies For Human Immunodeficiency Virus And Hepatitis C Virus Proteases, Yong Wang

Wayne State University Dissertations

The antiviral drug development has improved steadily to treat the infections of human immunodeficiency virus (HIV) and hepatitis C virus (HCV) which represent heavy public health burdens. The viral protease plays an indispensable role in viral maturation and therefore becomes one of the most important targets for drug design. Nine HIV-1 protease inhibitors and two HCV protease inhibitors have been developed and approved by the U.S. Food and Drug Administration. However, mutations in the protease decrease reduce the efficacy the drugs. In this study, the enzyme assays indicate that darunavir and tipranavir exhibit the most potent inhibition against the multi-drug …

Single Molecule Studies Of Rna-Target Interactions, Sharla Leann Wood

Wayne State University Dissertations

We have used FRET, single molecule spectroscopy, and several other biophysical techniques to study how the folding of RNA allows it to perform its various functions by recognizing and binding a target ligand. We have shown that the c-di-GMP riboswitch undergoes a large, global conformational change upon binding of the ligand. The folding dynamics of the c-di-GMP riboswitch upon Mg2+ binding help to pre-organize the aptamer for efficient ligand binding and ultimately efficient gene expression. We have also investigated two instances, a fluorophore-binding aptamer and molecular beacon, where the folding of RNA can be used to detect an analyte. We …

The Spliceosomal Protein Prp8 Stabilizes A Compact Conformation Of The U2-U6 Complex, Subasinghe Appuhamilage Lemintha Imali Subasinghe

Wayne State University Theses

The spliceosome is a large, RNA-protein complex that catalyzes pre-mRNA splicing during mRNA maturation. The RNA components (small nuclear RNA; snRNAs) of the spliceosome have been well studied and are believed to be involved in the splicing catalysis. Although proteins are essential for splicing, they may not be directly involved in catalysis. Among hundreds of proteins, Prp8 is the only protein that interacts with all of the catalytically important snRNAs. Therefore, it is hypothesized that Prp8 may catalyze splicing either by directly participating in catalysis or by stabilizing the conformation of the catalytically active spliceosome. In order to test whether …

Ultraviolet Resonance Raman Spectroscopy For Characterization Of Rna Structure And Thermodynamics, Joseph Dustin Handen

Legacy Theses & Dissertations (2009 - 2024)

Raman spectroscopy is a technique well suited for the study of biological molecules such as proteins, peptides, or RNAs. By utilizing an ultraviolet resonance Raman (UVRR) instrument, we are afforded a tremendous increase in sensitivity because of resonance enhancement. Additionally, this technique does not require any labeling. Moreover, this technique is better suited for studying biological systems than infrared absorption due to reduced interference from water. In this study, we apply techniques we have developed for the study of protein and peptide fibrillation to a model RNA homodimer. We demonstrate that UVRR spectroscopy is uniquely suited to monitoring the free …

Selection Of Chemically Modified Rna Aptamers Against The Glua2q Flop Ampa Receptor, Hyojung Seo

Legacy Theses & Dissertations (2009 - 2024)

The á-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors play an important role in neurotransmission and synaptic plasticity in the central nervous system. Excessive activity of these receptors has been implicated in some neurodegenerative diseases, such as Parkinson's disease, ischemic stroke and amyotrophic lateral sclerosis (ALS). AMPA receptor inhibitors are therefore drug candidates for potential treatment of these neurological disorders and diseases. The objective of my MS thesis work is to develop a stable aptamer so that it can be tested and used in vivo where the aptamer must be exposed to ribonucleases. To do this, I prepared a library containing RNAs with 2'-Fluoro …

Inhibition Of Glutamate Receptors By Constructing Bipartite Rna Aptamers, Jeffrey Hebert

Legacy Theses & Dissertations (2009 - 2024)

The relationship of excessive activity of AMPA-type glutamate receptors, and cell death, has long provided researchers a means of investigating neurodegenerative disorders, such as Parkinson's Disease (PD) and amyotrophic lateral sclerosis (ALS). Inhibitors of AMPA receptor channels, including chemical and nucleic acid molecules such as RNA aptamers, have served as potential therapeutic agents and treatment of neurodegenerative disorders. In this study, building bipartite aptamers to enhance inhibitory potency, as compared with a monomeric aptamer of AMPA receptor, is described. An enhanced potency is due, at least in part; to the proximity effect in bipartite structures or binding of a monomeric …

Mechanism Of Inhibition Of The Glua2 Receptors By N-3 Derivatives Of 2,3-Benzodiazepines With C-4 Methyl Group, Congzhou Wang

Legacy Theses & Dissertations (2009 - 2024)

α-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors are one of the three subtypes of ionotropic glutamate receptors. AMPA receptors mediate fast synaptic neurotransmission in the central nervous system (CNS). Over-activation of calcium permeable AMPA receptors causes intracellular calcium overload, which leads to neurodegeneration and cell death. As such, AMPA receptors have been implicated in a number of neurological disorders and diseases, such as epilepsy, amyotrophic lateral sclerosis (ALS), and Parkinson's disease. 2,3-Benzodiazepine derivatives (or GYKI compounds) are a group of structurally similar compounds synthesized as inhibitors of AMPA receptors, and they have been used as potential drug candidates for the treatment of various …

Interactions Of The Human Immunodeficiency Virus Type 1 Nucleocapsid Protein With Non-Hiv-Derived Nucleic Acids : Implications For The Viral Replication Cycle, Abhijit Padmakar Jadhav

Legacy Theses & Dissertations (2009 - 2024)

During attempts to develop aptamers that bind to the nucleocapsid protein of HIV-1 (i.e. NCp7) with high affinity, a heretofore unreported property of the protein--the ability to mediate degradation of nucleic acids, was discovered. Using λ DNA as a model nucleic acid system, it was shown that NCp7-mediated degradation of nucleic acids is non-specific, depends on incubation time, the concentration of NCp7, and the presence of divalent and monovalent cations. It was further demonstrated that degradation can be abrogated if NCp7 is pre-incubated with NCp7-inhibitors. Lyophilization of NCp7 can induce irreversible changes in its secondary structure that result in loss …

Amyloid Fibril Polymorphism : Structure, Supramolecular Chiraliy And Spontaneous Interconversion, Dzmitry Kurouski

Legacy Theses & Dissertations (2009 - 2024)

Specific protein aggregation has been linked to more than 25 severe human maladies including prion, Alzheimer's, and Parkinson's diseases. These important malfunctions are often referred to as 'conformational' disorders and result from the conversion of a normal isoform of a protein into a specific b-sheet rich polymeric amyloid form. This work elaborates a comprehensive characterization of amyloids and dedicated to the investigation of the fibril polymorphism using advanced microscopic tools, such as Atomic Force and Scanning Electron microcopies, together with several vibrational spectroscopy techniques, such as Raman, Infrared and Vibrational Circular Dichroism. A new type of protein folding-aggregation phenomenon, spontaneous …

Investigating The Glutamine-Trna (Glutamine) Synthesis Appartus Of The Human Pathogen Helicobacter Pylori, Nilesh Joshi

Wayne State University Theses

INVESTIGATING THE GLUTAMINE-TRNA (GLUTAMINE) SYNTHESIS APPARTUS OF THE HUMAN PATHOGEN HELICOBACTER PYLORI

by

NILESH JOSHI

August 2012

Advisor: Tamara L. Hendrickson

Major: Chemistry

Degree: Master of Science

Accurate protein biosynthesis is a vital process to all cellular life. Aminoacyl-tRNAs are at the heart of this process: A correctly formed aminoacyl-tRNA is critical for protein biosynthesis. Organisms have evolved many mechanisms to repair misacylated tRNAs before they cause errors in protein biosynthesis, thus maintaining the integrity of the genetic code. The human pathogen Helicobacter pylori (H. pylori) synthesizes Glu-tRNAGln as an intermediate to producing Gln-tRNAGln. This misacylated intermediate could cause lethal …

Why Do We Collect?, Allison Marsh

Section 2: Imaging the Microscopic

No abstract provided.

Spotlight On Usc: A.C. Moore Herbarium, Allison Marsh

Section 2: Imaging the Microscopic

No abstract provided.

Imaging And Aesthetics, Allison Marsh

Section 2: Imaging the Microscopic

No abstract provided.

Investigations Into Modulation Of Brain Oxidative Stress By Various Interventions, Jessica Lynn Harris

Theses and Dissertations--Chemistry

In this thesis study we examined glycogen synthase kinase-3β (GSK-3β) and its effects over Nrf2 and Pin 1 as it relates to Alzheimer’s disease (AD). AD is a neurodegenerative disease characterized by a prolonged high oxidative environment. Transcription factor Nrf2 is vital in the brain’s defense against oxidative insults through its up-regulation of over 100 antioxidants. Depletion of the brain’s antioxidant defense system results in intolerance to an oxidative environment, contributing to the progression of AD. The regulatory Pin 1 protein promotes cellular homeostasis, and when down-regulated results in increased deposits of neurofibrillary tangles (NFTs) and amyloid-β (Aβ) plaques, the …

Bifunctional Bisphosphonates For Delivering Biomolecules To Bone, Jivan N. Yewle

Theses and Dissertations--Chemistry

Active targeting with controlled delivery of therapeutic agents to bone is an ideal approach for treatment of several bone diseases. Since bisphosphonates (BPs) are known to have high affinity to bone mineral and are being widely used in treatment of osteoporosis, they are well-suited for drug targeting to bone. For this purpose, bifunctional hydrazine-bisphosphonates (HBPs) with spacers of various lengths and lipophilicity were synthesized and studied. Crystal growth inhibition assays demonstrated that the HBPs with shorter spacers bound more strongly to bone mineral, hydroxyapatite (HA), than did alendronate. HBPs were also demonstrated to be non-toxic to MC3T3-E1 pre-osteoblasts. The targeted …

Spontaneous Cooperative Assembly Of Replicative Catalytic Rna Systems, Nilesh Vaidya

Dissertations and Theses

The RNA World hypothesis proposes a period of time during the origins of life in which RNA molecules were the only source of both genotypes and phenotypes. Although a vast amount of evidence has been obtained in support of this hypothesis, a few critical demonstrations are lacking. A most crucial one is a demonstration of self-replication of RNA molecule from prebiotic soup. Previously in the Lehman laboratory, it has been demonstrated that a 198-nucleotide molecule derived from the Azoarcus group I intron can self-assemble from up to four fragments of RNA via recombination. Furthermore, the covalent full-length molecules are catalytically …

A Novel Method Of Studying Ion Formation And Fragmentation Using A Modified Time-Of-Flight Mass Spectrometer, David S. Ames

Dissertations and Theses @ UNI

Laser desorption has been an important tool in mass spectrometry. It has been known that an order of magnitude more neutrals than ions are produced during laser desorption. A Time-Of-Flight Mass Spectrometer with an infinitely adjustable acceleration region was constructed to map the population distribution of neutral ion precursors and metastable ions in the flight tube. Desorption was performed by using a nitrogen UV laser at 337 nm. Experiments conclude that the majority of post-source ionization of neutrals occurs approximately 2.5 cm from the sample-laser interface. The intensity of ions tapers rapidly out to 6.0 cm, however ions were detected …