Dept of Chemistry
404 Crosley Tower
Ph: (513) 556-9200
Fax: (513) 556-9239
Topic: Epitranscriptomics of RNA chemical modifications
I am interested in development and demonstration of the utility of various molecular tools and technologies associated with epitranscriptomics of coding and noncoding RNA. These include development of enzymes for qualitative and quantitative determination of chemical modifications in RNA by mass spectrometry or RNA-seq type of high-throughput approaches, and development of bait molecules for isolating target RNAs from complex biological mixtures. These novel and high-throughput approaches will expand and enhance the currently available strategies for understanding the functional significance of a variety of chemical modifications in RNA nucleosides, termed as epitranscriptomics. The REU student engaged in such research studies will learn various bioanalytical and molecular biology techniques for analysis of RNA structure and function, thereby gaining experience in biochemistry and bioanalytical chemistry of RNA and proteins, their purification, and mass spectrometry. This endeavor will help the REU student in understanding the interphase of chemistry and biology associated with molecular processes of gene expression and epigenetic regulation.
The use of polymers in society has become ubiquitous, from commodity items to high technology and cutting-edge therapeutics and diagnostics. The research in our group is focused on synthetic chemistry approaches to studying new biomaterials. Specifically, we are interested in blood-contacting biomaterials and co-polymer foams. To accomplish our goals, we use polymer chemistry to mimic naturally occurring biological macromolecules. In addition to uses as new biomaterials, the polymers prepared in our group can be used as shape-memory polymers, self-healing materials, gel-forming materials, and rheology modifiers. REU students in our group will contribute to using this chemistry to prepare polymers designed for determining the structure/activity relationships of synthetic heparin mimics. This project will result in a rationally designed set of materials with precise architecture and functional groups that will provide new, fundamental insights into polymer/host interactions. Students involved in this project will gain experience in polymer synthesis and characterization techniques, experimental design, and problem solving techniques.
Our research group works in the areas of theoretical and computational chemistry, employing fundamental ideas from statistical mechanics, quantum mechanics, and thermodynamics to study a range of condensed phase problems. These problems include the basic aspects of ion solvation in water and near interfaces, ions in organic solvents used in lithium ion batteries and supercapacitors, and the biophysics of ion channels. We are also developing new theoretical and computational methods to examine these problems. Several projects are available for an REU summer student: 1) molecular dynamics simulations of ions in large water clusters, 2) related simulations of ions in ethylene carbonate and propylene carbonate, and 3) theory and modeling of ions in binding sites in chloride channels and transporters. The student would gain extensive experience in modeling complicated liquids, interfacial systems, and/or proteins. The work has a direct impact on gaining a better understanding of ionic solutions, energy storage, and ion binding and transport in biological systems.
Bill Connick (Co-PI)
Participants working in our group will synthesize and investigate new hybrid materials that undergo a reversible color change upon exposure to chemical vapors and aqueous analytes. These materials have potential practical use in chemical sensing applications, including workplace safety, environmental monitoring, and detection of illicit drugs and weapons. The research leverages our experience with colorimetric vapor-sensing materials, as well as our discovery of molecular materials that respond with extraordinary selectivity to anions in aqueous solution. For example, [Pt(tpy)Cl](PF6) undergoes a rapid and distinct color change in the presence of aqueous perchlorate ion, which is an important ground water contaminant near military installations (Figure 1). Upon exposure, the salt undergoes anion exchange, resulting in a pronounced color change and dramatic red-shift in luminescence. When supported in mesoporous particles embedded in a polymer, the response is remarkably sensitive (≥1 ppb) and selective. For example, no color change occurs upon exposure to common interferents, including halides, nitrate, phosphate, carbonate, or sulfate. The objective of this research is to elucidate the factors that govern the colorimetric and luminescence-based response of d8-electron metal complex salts to vapors and aqueous anions. A detailed understanding of the response of these types of materials, as well as the influence of the surrounding medium and supporting material, is an essential first step toward incorporation in chemical sensing devices. These results will have a significant positive impact, as the identified factors are expected to not only advance understanding of colorimetric materials, but also fundamentally advance the fields of chemical sensing and materials science. The REU students contributing to this research will gain experience in organic and inorganic synthesis, as well as a wide range of physical methods, including X-ray crystallography, MS, NMR spectroscopy, TGA, DSC, SEM/ESEM, AFM, ITC, FTIR-ATR, and QCM gravimetry.
Our group is engaged in fundamental research related to the thermodynamics and kinetics of biopolymers. There are two main lines of research, both involving the study of biological assemblies whose action involves conversion of chemical energy into mechanical energy. The first direction is related to the action of molecular machines called chaperones that assist or direct the remodeling of either newly synthesized proteins or misfolded proteins due to stresses such as heat or chemical denaturation. The second direction is related to deciphering the mechanism of action of molecular motors on cytoskeletal filaments during fundamental cellular processes such as mitosis or axonal and dendrites growth. The research is directed at developing new computational approaches for modeling the mechanical response of large protein complexes under various cellular conditions, leading to fundamental insight into the role played by forces in the life of the cell. External tension is applied to cells during processes such as cell–cell adhesion, blood flow, wound closure, axonal growth, and mitosis. As a result, force-induced changes occur in cytoskeletal proteins, leading to the deformation of cells and transduction of mechanical signals into biochemical signals, ultimately inducing biological responses such as alterations in specific gene expression, changes in protein synthesis, and channel activation. A project for an REU student is "Computational modeling of the action of molecular machines during stress application in cells". The goal of this project is to determine the changes in the mechanical response of protein–protein interactions between molecular machines, such as chaperones and substrate proteins, or molecular motors, such as kinesins and cytoskeletal filaments, that allow the cell to respond and adapt to the action of mechanical forces. A student involved in this project will become familiar with the computational methodology behind realistic modeling of proteins and their cellular environment (water, ions), learn how to use visualization tools for large biomolecules, become familiar with protein databases, and gain extensive knowledge in searching the scientific literature.
The research in our group lies at the interface between inorganic and organic chemistry, focusing on the development of homogeneous catalysts based on first-row transition metals such as nickel, cobalt, iron, and copper. Such efforts are motivated by the fact that precious metals, which are widely used today in catalysis for synthesizing commodity and specialty chemicals, are expensive, limited in supply, and sometimes difficult to remove from organic products. The challenge of using first-row transition metals for catalysis starts with the difficulty in identifying ligands that can not only bind tightly to the metals but also promote precious metal-like reactivity or de-emphasize the metal’s role. Our investigation of pincer-ligated metal hydrides has led to the discovery of nickel- and iron-based catalysts for the hydroboration of CO2 to methanol derivatives and the hydrogenation of fatty acid methyl esters to fatty alcohols. Our ongoing projects build on these initial successes and focus on the improvement of catalytic efficiencies through further modification of the catalyst structures. REU students involved in these projects will learn various synthetic techniques, including the handling of air- and moisture-sensitive compounds. They will also be trained to conduct mechanistic studies using NMR spectroscopy, X-ray crystallography, and chemical kinetics. Furthermore, the research projects will teach students the concept of increasing energy efficiency by performing catalytic reactions and the notion of sustainability by using renewable feedstock and readily available materials.
Anna Gudmundsdottir (PI)
One of the greatest challenges of the 21st century is the development of sustainable energy to maintain the needs of society. One of the major thrusts has been to harness solar energy as a clean, renewable energy source. Thus, the development of solid-state photodevices is vital for developing sustainable energy, which requires an advanced understanding of the fundamentals of solid-state photophysics and photochemistry. Our research group is studying the fundamentals of solid-state photochemistry, and currently, we are investigating the release of N2 molecules from crystalline naphthoquinone diazido derivatives. Upon exposure to light, diazido crystals dance around and release N2 atoms, and we are working toward correlating the rate of release or dancing with the crystal packing of the starting material. An REU student would spend the summer being trained to synthesize new diazido derivatives and study the mechanism of their photoreactivity using transient spectroscopy and product studies. The proposed research would allow the student to become familiar with using various spectroscopic methods, such as NMR, IR, and UV absorption.
The research focus of our group is the development and understanding of solvent-free organic reactions. In our research laboratory, we employ the novel solvent-free technique of mechanochemistry. Under this process, we use a high-velocity ball bearing to pulverize particles to the point that a reaction occurs. In addition to conducting solventless reactions, we also design our reactions such that they are environmentally friendly. Our purification procedure tries to minimize the use of harmful solvents, both in the reaction as well as at the purification stage. To create a new generation of environmentally conscious chemists that think of the environmental ramifications alongside the potential solutions to scientific problems, aspects of green chemistry must be taught early in their careers. REU students in our laboratory will work on various reactions using mechanochemistry and learn various aspects of green chemistry. Given the novelty of the technique, there are opportunities for the results of an REU student to be published in prominent scientific journals and presented at scientific meetings. Betsegaw Lemma, an NSF REU student in my research group recently co-authored a paper in Green Chemistry based on the research he conducted as an REU student in my lab. This research began a fruitful collaboration with Prof. Michael Coleman, Betsgaw’s undergraduate advisor. Since then, Professor Coleman, two more recent REU students, Sara Pilson and Devonna Leslie, and I published our latest collaborative project in Angew. Chem.7 We are currently in the process of submitting another manuscript based on their REU research.10 Many of my research papers have undergraduate students as co-authors, and I am a firm believer in incorporating undergraduate students fully into my research projects.
Reactive Oxygen Responsive Self-Cyclization for Detection and Bio-Activation. Though the terms excessive reactive oxygen species (ROS) and oxidative stress are widely used, their biochemical basis and methods to utilize this unique environment remain limited. The most useful definition put forward has been that excessive ROS is a state with a disruption in ROS signaling and control. Importantly, ROS molecules tend to be transient, hard to detect, and location-specific, resulting in a lack of a chemical understanding of this key cellular process. Current detection and activation strategies rely on Chan–Lam-type coupling, where a phenol in a bioactive molecule is replaced with a boronic ester. A low signal occurs when the boronic ester is present and reaction in oxidative environments leads to formation of the active phenol. There are several issues with this method, including (1) high rates of reactivity with ROS, (2) limited substrate scope restricted to a phenol, and (3) limited ability to tune the rate of activation to address detection in alternative environments. To overcome these issues, we have designed self-cyclizing ROS-responsive antioxidants. We covalently attach an intact bioactive molecule at a key alcohol or amine (either alkyl or aryl) to the antioxidant. This attachment leads to a loss of activity. In high ROS environments, the antioxidant self-cyclizes and releases the bioactive molecule. We have the ability to tune the rate of reaction by changing the substituents in the self-cyclizing ROS-responsive antioxidant. As part of the REU program, students will synthesize self-cyclizing ROS-responsive antioxidants to alter the rate of reaction or enhance substrate scope. In addition, more biologically inclined REU students will determine the activation rates (Km and Vmax) in the presence of biologically relevant oxidases and within cells.
Research in our group lies at the biological/nanoscience interface and is focused on the development of new plasmonic bionanomaterials for both biosensing and biophysical/spectroscopy studies. Materials of interest combine biological species, such as proteins and DNA, with noble metal nanoparticles and substrate-bound nanoparticle arrays. Our research employs a wide range of techniques, such as protein expression, nanoparticle synthesis, and surface nanofabrication to make the samples, AFM and TEM to characterize the samples, and plasmon absorption and surface enhanced Raman spectroscopy (SERS) to utilize the samples. An REU student in our group will work on a project utilizing localized surface plasmon resonance (LSPR) for biosensing. This technique shows great promise in sensitive, colorimetric, label-free detection of biomarkers for disease diagnostics. We have recently shown that uniform nanoparticle arrays can be incorporated into microfluidic and multiplexed devices for rapid, portable biological assays. Such fabrication has also been carried out on flexible plastic substrates, which allow one to facilely change nanoparticle shape and spacing by simply bending or stretching the underlying substrate. The REU student will work with these nanoparticle arrays on flexible plastic substrates and assess their sensitivity for applications in diagnostic biological assays. The student working on this project will gain knowledge of nanofabrication, photolithography, noble metal nanoparticles, LSPR, and spectroscopy.
Research in our group is focused on computational modeling of biological nanomachines involved in protein degradation. Protein quality control, such as degradation mechanisms, prevents deleterious off-pathway reactions of misfolding or aggregation. In the degradation pathway, AAA+ (ATPases associated with various cellular activities) nanomachines, such as bacterial caseinolytic protease (Clp) ATPases, unfold and translocate substrate proteins (SPs) through narrow central pores as a prerequisite for the ultimate destruction of the polypeptide chain within the peptidase chamber. Understanding the protein remodeling mechanisms of these biological nanomachines is of central importance for deciphering the details of cellular processes. A specific project for an REU student will concern probing the dependence of the Clp ATPase unfoldase function on the direction of applied mechanical force. Multiscale modeling of Clp-mediated unfolding of SPs with discernible mechanical anisotropy will yield detailed information of these properties. We propose to probe mechanisms of unfolding and translocation along the restricted direction of the N–C termini. The SPs to be studied will include wild-type and variants of proteins probed in single-molecule experiments. Unfolding and translocation pathways obtained in these studies will be contrasted with those in multidirectional pulling geometries, which mimic the cellular environment. Interactions between the Clp ATPase and SPs will probe multiple orientations of the substrate. The student working on this project will gain knowledge concerning biomolecular simulations of nanomachines and use of computational tools for visualization and analysis of biomolecular structures.
Research in our group will expose REU students to nanomaterial science. Specifically, the students will participate in the ongoing development of nanomaterials for sensing and therapeutic applications. This will be built upon our recent successes in synthesizing nanoparticle-based photosensitizers for photodynamic antibacterial and anticancer therapy, and metal nanoparticles for chemical and biochemical sensing. For instance, we have demonstrated that nanoparticle-based photosensitizers can achieve very high efficiency (up to a million-fold over the respective molecular photosensitizers) in photoinactivating a broad spectrum of bacteria, including drug-resistant ones. Our ongoing efforts focus on testing the antifungal activity of these photosensitizers and developing devices integrating these photosensitizers for infection management. The REU students will work closely with senior group members and me personally at the beginning of the program and transition into more independent study as they become more experienced. The REU students will be trained to conduct experiments such as nanoparticle synthesis, various spectroscopies, and bioassays.