2013 Summer Research Projects
Gold-catalyzed Rearrangement of N-Propargyloxypyridines
Professor Carolyn Anderson and John LaGrand
Organic synthesis is a powerful technique that allows access to a wide range of different structural motifs. In this project, we are working to advance a method for the synthesis of N-substituted pyridones; an interesting functional group found in a series of pharmacologically interesting compounds. To date, we have developed a new gold(III)-catalyzed method for accessing this motif by rearranging a related system. The student working in this area will be responsible for exploring and optimizing a related gold(I)-catalyzed rearrangement.
Synthesis of N-Alkyl Pyridone Containing β- and γ-Amino Acids
Professor Carolyn Anderson and David Wierenga
Organic synthesis is a powerful technique that allows access to a wide range of different structural motifs. In this project, we are working to develop a method for the synthesis of N-alkyl pyridone containing β- and γ-amino acids – homologues of the natural amino acids, which contain an interesting functional group, found in a series of pharmacologically active compounds. To date, we have discovered an important intermediate in route to these species and have begun to optimize its synthesis. The students working in this area will continue to seek conditions for the preparation of this intermediate and its conversion into the desired amino acids.
Watching Membrane Proteins in Real Time
Prof. Eric Arnoys, Riemer Praamsma and Kathryn Wrobel
We will characterize the behavior of several membrane-bound proteins in living cells with state-of-the-art techniques to examine their cellular localization, mobility, and interactions with other proteins. Protein targets have been tagged with fluorescent proteins so that they can be viewed in living systems. We will also examine what effect extracellular signals have on the proteins' behavior. The student will serve as a research collaborator, learning both common and state-of-the-art biochemistry experimental techniques. In addition to learning about how research works, he or she will also gain valuable experience and will have the opportunity to serve as a co-author on research papers. No previous research experience or biochemistry coursework is required; a love of lab work and at least one college-level chemistry course are a must. First year science students interested in a multi-year research experience are strongly encouraged to apply.
Preparation of Bicyclo[1.1.1]pentyl Stannanes, Silanes and Trifluoroborates and Applications in Palladium-Catalyzed Cross Coupling Reactions
Prof. Michael Barbachyn and Niecia Flikweert
This research proposal focuses on the preparation of bicyclo[1.1.1]pentyl (BCP) stannanes, hypervalent silanes and trifluoroborates followed by an exploration of the palladium-mediated cross-coupling reactions of these substances. Initially, reliable synthetic protocols for the preparation of a range of BCP stannanes, silanes and trifluoroborates will be explored and optimized. The targeted BCP cross-coupled products are envisioned as useful intermediates for further synthetic transformations, leading to potential applications in a variety of distinct research areas. Of greatest interest is the incorporation of selected BCP subunits into known LpxC inhibitor scaffolds to yield antibacterial agents with potentially potent activity against multidrug-resistant Gram-negative bacteria such as Pseudomonas aeruginosa. LpxC [UDP-3-O-(R-3- hydroxymyristoyl)-GlcNAc deacetylase] is an essential metalloamidase that catalyzes the first committed step in the biosynthesis of the lipid A component of lipopolysaccharides in the bacterium's outer membrane. Any synthesized LpxC inhibitors will be evaluated for their antibacterial activity potential, potentially by a microbiologist at Calvin but most likely at the University of Notre Dame (Marvin Miller's lab).
Synthesis of Novel QPT Antibacterial Agents Bearing Substitution at the Benzylic Position
Prof. Michael Barbachyn and John Elenbaas
The quinoline pyrimidinetriones (QPTs) are a novel class of bacterial topoisomerase inhibitors that were discovered in 2002 and subsequently reported in the open literature in 2008 (Miller, A.A.; et al. Antimicrob. Agents Chemother. 2008, 52, 2806-2812). The initial lead compound, PNU-286607, exhibited excellent in vitro activity and in vivo efficacy against problematic Gram-positive pathogens, including methicillin-resistant Staphylococcus aureus (MRSA). This research project will focus on developing new synthetic methodology to synthesize QPT analogs substituted at the benzylic position, an area that has not been previously explored. Any synthesized analogs will be evaluated for their antibacterial activity potential, potentially by a microbiologist at Calvin but most likely at the University of Notre Dame (Marvin Miller's lab).
Anti-Oxidant Nature of Tyrosine-Cysteine Crosslinks in BF4112
Prof. David Benson and Taylor Hegg
The covalent bond between tyrosine and cysteine amino acid sidechains in proteins could potentially provide anti-oxidant chemistry. This project will characterize how the covalent bond (crosslink) between a tyrosine and cysteine in an orphan protein (BF4112) occurs. Our research group found this crosslink for the first time, but we are using this protein to "test drive" a variety of formation chemistries. We are interested in copper, iron, and manganese-based oxidations that are biologically inspired.
Anti-Oxidant Nature of Tyrosine-Cysteine Crosslinks in Cysteine Dioxygenase
Prof. David Benson and Brett DeVries
The covalent bond between tyrosine and cysteine amino acid sidechains in proteins could potentially provide anti-oxidant chemistry. This project will characterize how the covalent bond (crosslink) between a tyrosine and cysteine in human cysteine dioxygenase (CDO) functions. Mammalian CDOs contain a tyrosine-cysteine crosslink where cysteine is oxidized but it is not clear if this crosslink contributes to the chemistry or if it contributes an additional function. We believe an additional anti-oxidant function in CDO controls how long the protein survives in the cell which is used to regulate cysteine concentrations in the cell. Some cysteine is necessary for protein production but too much cysteine contributes to neurological diseases.
Analysis of Tyrosine-Cysteine Crosslinks Concentrations in Proteins
Prof. David Benson and Emily Golz
The covalent bond between tyrosine and cysteine amino acid sidechains in proteins could potentially provide anti-oxidant chemistry. To date, the most quantitative assay for tyrosine-cysteine crosslink concentration comes from a mobility shift assay in gel electrophoresis. A more quantitative assay needs to be developed. Our research group has explored absorbance, fluorescence, colorimetric, and electrochemical assays and has found encouraging results from a fluorescence assay. This project will collect the final data for calibration curve and apply this assay to BF4112, cysteine dioxygenase, and hemoglobin.
Computational Analysis of Tyrosine-Cysteine Crosslinks in Proteins
Prof. David Benson and Matt Hollowell
The covalent bond between tyrosine and cysteine amino acid sidechains in proteins could potentially provide anti-oxidant chemistry. We have found at least one new tyrosine-cysteine crosslinked protein from a simplistic computational search of the protein databank (PDB), which houses all reported protein structures. Our research group is looking for better method to refine this list of potential proteins, and find additional proteins from the PDB, that might contain tyrosine-cysteine crosslinks. The work will involve running molecular dynamics calculations on Unix operating systems; which I have experience with.
NMR Analysis of Tyrosine-Cysteine Crosslinks in Proteins
Prof. David Benson and Andrew Roth
The covalent bond between tyrosine and cysteine amino acid sidechains in proteins could potentially provide anti-oxidant chemistry. To date, the only structural information for tyrosine-cysteine crosslink has been derived from X-ray crystallography. We are pursuing X-ray structure analysis of a new protein with a tyrosine-cysteine crosslink, but NMR can provide more rapid information. This work will use the 500 MHz NMR at Calvin to directly demonstrate formation of a tyrosine-cysteine crosslink within an intact protein and additional structural information.
Cooperativity in Hydrogen Bonding
Prof. Roger DeKock and John Strikwerda
For several years we have performed theoretical studies that relate to cooperativity in hydrogen bonding. For example, we examine molecular cubes with the formula NH3(H2O)7. We believe that these small cubes can serve as prototypes for cooperativity in hydrogen bonded networks in real chemical systems, such as ammonia, NH3, in water. We have completed similar studies on the thirty nine cubes of HF(H2O)7. Additional studies on these systems need to be completed. Those additional studies would be the focus of the summer 2013 work.
Sequential Ionization Energies of Atoms
Prof. Roger DeKock and Jared Weidman
For several years we have performed theoretical studies in order to obtain insight into the electronic structure of atoms. Specifically we aim to provide a theoretical underpinning as to why the sequential ionization energies of atoms roughly follow an arithmetic progression. We employ the GAMESS software, and the Restricted Open Shell Hartree Fock model within GAMESS (General Atomic and Molecular Electronic Structure System).
Faculty approaches to student interaction in teaching science, math, and engineering
Prof. Herb Fynewever, Paula Kuiper and Rachel VanOeffelen
Usually when students are learning science, math, and engineering they reveal their thinking to the instructor and the instructor uses this information to give feedback to the students. Often, however, this two-way communication is limited to formal assessments such as quizzes and exams, which happen after most of the learning has happened. Research has shown that there are many effective ways to better integrate this communication into the learning process (e.g. interactive classroom delivery and activity) realizing significant gains in student learning. Further research is needed to determine what the barriers are to two-way communication and to devise strategies to remedy these barriers. In this research, students will analyze data from classroom observations and interviews with faculty and students to detect and classify these barriers.
Detection of oligomers of GLUT1 and its relationship to the activity of the transporter
Prof. Larry Louters and Ola-Oluwakiti Alabi
One model to explain the activation of GLUT1 is that it becomes more active if the transporter aggregates, likely as a tetramer. We will use two techniques to try to isolate GLUT1 tetramers and determine if the concentration of these tetramers changes when glucose uptake is activate. The first method is called blue native PAGE, which, in contrast to SDS-PAGE, is an electrophoretic technique capable of isolating membrane protein complexes intact. The second method will be using chemical crosslinking reagents that covalently link the GLUT1 proteins together, which can be then separated and sized by SDS-PAGE.
Relationship of GLUT1 tethering to the cytoskeleton and its influence on its activity
Prof. Larry Louters and Sam Kerk
GLUT1, like many membrane proteins, can be tethered to the cell cytoskeleton by connector proteins. Typically this tethering is involve in the recycling of the protein to and from the membrane surface. We will measure the fraction of GLUT1 tethered to the cytoskeleton and determine if that fraction changes when GLUT1 is activated.
Effects of curcumin (from the spice, tumeric) on glucose uptake
Prof. Larry Louters and Stephen Gunnink
Curcumin, an ingredient in the Indian spice, tumeric, has a molcular structure that is reactive with thiols. GLUT1, the major glucose transporter, is thought to be activated by the formation of a disulfide bond. We hypothesize that curcumin will alter the glucose transport activity of GLUT1 in L929 fibroblast cells.
Photochemistry: Research in Fluorescence in Sycamore Wood and Photoelimination in Acetylacetone
Prof. Mark Muyskens, Andrea Bootsma and Alexandria Hoerr
There are two areas of photochemistry that will be investigated. One area is to investigate the chemical structure of the highly fluorescent components of the aqueous extract of sycamore wood. This project continues an effort to identify the fluorescent compounds from sycamore wood. The work involves liquid chromatography for separation and fluorescence spectroscopy. The other project will use computational tools to model the kinetic and molecular structural details of a gas-phase photochemical reaction. My research has experimental results from the ultraviolet laser photoelimination of hydrogen fluoride fromfluorine containing acetylacetone in the gas phase. The work will be greatly assisted by developing models related to the data.
Investigating the Binding of Insulin with G-Quadruplex DNA
Prof. Kumar Sinniah, Maggie Van Winkle, Nicole Michmerhuizen and Amanda Witte
G-quadruplexes are noncanonical DNA structures formed from guanine-rich DNA sequences in the presence of monovalent cations such as potassium or sodium ions. These structures are of significant interest due to their role in biological processes. The human genome contains hundreds of thousands of sequences that have the potential to form quadruplexes. Proteins that bind to G-quadruplex DNA are likely to provide a clue to the role of G-quadruplex DNA in biology. Our group is currently studying the biophysical interactions between the protein insulin and the various sequences of G-quadruplex DNA found in the insulin linked polymorphic region. This project is suitable for a student interested in biochemistry, chemistry, or biology.
Characterizing Riboflavin Conjugated Nanoparticles for Targeted Drug Delivery in Cancer Therapy
Prof. Kumar Sinniah, Abby Leistra and Jong Hyun Han
Riboflavin (RF) receptors have been found to overexpress in prostate and breast cancer cells. RF receptors can be targeted for selective delivery of anticancer drug molecules. Our group has characterized RF conjugated dendrimer series for targeting the RF receptor. We determined that one series of dendrimer conjugates based on the orientation of RF attachment to the dendrimer performed better at binding to the RF receptor. This summer we hope to extend this work to study both monovalent and multivalent interactions between RF and its receptor using single molecule and bulk ensemble methods. This project is suitable for a student interested in biomedicine/biochemistry/chemistry/biology/bioengineering.
Perturbation of Acidity via Noncovalent Interactions
Prof. Chad Tatko and Caleb Uitvlugt
A structured environment or lipid association can result in a significant alteration. This project will construct a series of folded peptides into a beta-hairpin conformation. This co-localizes a queried amino acid proximal to an acid. Through NMR methods the pKa of the acid will be determined to elaborate the noncovalent impact of the neighbor.
Nanomolecular Building Projects
Prof. Doug Vander Griend, SeongEun Kim, Emily Rhude and Matt Haveman
Understanding and controlling the synthesis of supramolecules is a key goal of nanotechnology. Students working on this project will use UV-vis spectroscopy and mass spectrometry to investigate the solution chemistry of various inorganic and biochemical systems in which individual molecules associate in solution to form larger structures. Students may also get involved with computer programming and modeling if so desired.