About the Department
Abstracts for Seminars — Fall 2016
Fu-Sen Liang, University of New Mexico
Mammalian Cell Engineering via Chemical Reactivity Induced Protein Proximity
Synthetic biology aims to rewire biological systems in order to understand and control the functions of cellular systems that ultimately lead to novel therapies. We recently developed a new chemical strategy that integrates reactivity-based signal sensing and chemically induced protein dimerization to translate external signals in cellular environments into tailored biological events in the cells. In this seminar, our efforts in this research direction will be discussed. We expect that this strategy can be generally applied to reprogram mammalian cells to generate user-chosen biological outputs in response to combinations of cellular signals in pre-defined manners. We are applying this technology to develop new therapies for cancers and neurodegenerative diseases.
Dr. Liang received his BS in Chemistry from the National Taiwan University and continued his MS research on natural product synthesis in Dr. Tse-Lok Ho’s lab at the National Chiao Tung University. He then joined the Scripps Research Institute in La Jolla for PhD studies in Dr. Chi-Huey Wong's group where he synthesized and studied RNA-targeting small molecules. He did a postdoctoral research with Dr. Gerald Crabtree at Stanford University on chromatin remodeling complex and chemically induced proximity technology. He started his independent career at the University of New Mexico in 2012. His current research focuses on the development of new chemical strategies to facilitate the research in mammalian synthetic biology and microRNA regulation.
Yi Lu, University of Illinois, Urbana-Champaign
Design and Selection of Metalloenzymes and their Applications as Biocatalysts in Alternative Energies and as Biosensors in Environmental Monitoring, Medical Diagnostics and Imaging
Metalloenzymes play important roles in numerous biological processes. Designing metalloenzymes is an ultimate test of our knowledge about metalloenzymes and can result in new biocatalysts for practical applications such as in alternatives energies. We have been focusing ways to design heteronuclear metalloenzymes involved in multiple electron redox processes, such as heme-copper oxidase, heme-non-hem iron nitric oxide reductase and heme-[4Fe4S] cluster sulfite reductase. In the process, we demonstrate, while reproducing the primary coordination sphere may be good enough to make structural models of metalloproteins, careful design of the non-covalent secondary coordination sphere interactions, such as hydrophobicity and hydrogen bonding interactions, including those involving waters, are required to create functional metalloenzymes with high activity and turnover numbers comparable to those of native enzymes. While metalloproteins have been the major focus of metalloenzyme research for decades, metallo-DNAzymes, DNA molecules containing metal ions at the active site and displaying enzymatic activities, have emerged as a new class of metalloenzymes. We have been using in vitro selection to obtain from a large DNA library DNAzymes that are specific for metal ions and use spectroscopic methods to elucidate how and why DNAzymes can recognize metal ions selectively. We have also converted these DNAzymes into highly sensitive and selective sensors for metal ions, including those metal ions that are difficult to design using other methods, and demonstrated their applications in environmental monitoring, food safety, and medical diagnostics. The use of these metal-DNAzymes for imaging metal ions in living cells has also been established.
Dr. Yi Lu received his B.S. degree from Peking University in 1986, and Ph.D. degree from University of California at Los Angeles in 1992. After two years of postdoctoral research in Professor Harry B. Gray group at the Caltech, Dr. Lu started his own independent career in the Department of Chemistry at the University of Illinois at Urbana Champaign in 1994. He is now Jay and Ann Schenck Professor of Chemistry in the Departments of Chemistry, Biochemistry, Bioengineering and Materials Science and Engineering. He is also a member of the Center for Biophysics and Computational Biology, Beckman Institute for Advanced Science and Technology and Institute of Genomic Biology. His research interests lie at the interface between chemistry and biology. Specific areas of current interests include a) design and engineering of functional metalloproteins as environmentally benign catalysts in renewable energy generation and pharmaceuticals; b) Fundamental understanding of DNAzymes and their applications in environmental monitoring, medical diagnostics, and targeted drug delivery; and c) Employing principles from biology for directed assembly of nanomaterials with controlled morphologies and its applications in imaging and medicine. Dr. Lu has received numerous research and teaching awards, including the Royal Society of Chemistry Applied Inorganic Chemistry Award (2015), Fellow of the Royal Society of Chemistry (2015), and has been named to the Thomson Reuters Highly Cited Researchers list for 2015.
Jay Schneekloth, Jr., National Cancer Institute
Targeting Functionally and Structurally Diverse RNAs with Druglike Small Molecules
RNA governs an increasingly diverse number of biological processes related to normal cellular homeostasis as well as disease biology. Although small molecules that bind to and perturb the function of RNA would be highly valuable as probes and potentially as therapeutics, RNA remains a challenging target for small molecules. To address this problem, we have developed a small molecule microarray screening platform to identify druglike small molecules that bind to and perturb the function of specific nucleic acid secondary structures such as hairpins or quadruplexes. We use this approach to screen over 25,000 compounds against multiple oligonucleotide targets simultaneously. This seminar will focus on the application of the SMM platform to identify small molecules that bind to noncoding DNA and RNA sequences and modulate their function. Several targets will be discussed, including the discovery of selective inhibitors for the MYC promoter G-quadruplex, the HIV TAR hairpin, and riboswitches.
John "Jay" Schneekloth completed his undergraduate training at Dartmouth College in 2001, where he worked in the laboratory of Gordon W. Gribble. He then moved to Yale University, where he received his Ph.D. in the laboratory of Craig Crews studying natural product synthesis and mechanism of action, and helped developed the PROTAC technology for selective protein degradation in cells. Jay then pursued postdoctoral training with Erik Sorensen at Princeton University, where he developed a variant of the Ugi reaction. Jay was recruited to the Chemical Biology Laboratory at the NCI in 2011 as a tenure track investigator. His group uses chemical, structural, and biochemical approaches to identify probes of cellular pathways important to gene expression and cancer progression. Specific areas of focus in the lab include the study of small molecule probes of the small ubiquitin-like modifier (SUMO) pathway of posttranslational modification and the study of small molecules that bind to and perturb the function of RNA structures. A particular strength of the Schneekloth lab has been to use synthetic chemical approaches in concert with internally developed novel screening technologies to identify inhibitors of highly challenging, biologically valuable targets.
O. Anatole Lilienfeld, University of Basel
Quantum Mechanics, Chemical Space, and Machine Learning
Many of the most relevant chemical properties of matter depend explicitly on atomistic details, rendering a first principles approach mandatory. Alas, even when using high-performance computers, brute force high throughput screening of compounds is beyond any capacity for all but the simplest systems and properties due to the combinatorial nature of chemical space, i.e. all compositional, constitutional, and conformational isomers. Consequently, efficient exploration algorithms need to exploit all implicit redundancies present in chemical space. I will discuss recently developed statistical learning approaches for interpolating quantum mechanical observables in compositional and constitutional space.
Gregory S. Walker, Pfizer
The Role of NMR in Discovery Drug Metabolism: Where Are We Now and What Is the Future
Before the advent of micro cryo-probes the role of NMR in drug metabolism was often reserved for later stage drug development studies where structural identification of a metabolite was critical to drug registration. Over the last decade, concomitant with the development of micro cryo-probes, multiple advancements in the in vitro generation and isolation of metabolites have also occurred. These two technical developments enabled NMR to routinely address structural characterization of isolated metabolites in the low nanomole range. For the drug metabolism scientist, these new levels of sensitivity moved NMR as an analytical technique from drug development to drug discovery, greatly expanding the influence of NMR data. Also during this time period was a "rediscovery" of the quantitative nature of NMR. This enabled the quantification of these isolated materials to form standards of known concentrations and structures that could be used in a variety of pharmacological and metabolic studies. In this talk advantages and limitations of this process will be presented, along with several examples where NMR characterization and quantitation of a metabolite have provided data critical to drug discovery.
Melissa A. Pasquinelli, North Carolina State University
Sustainable Polymer Science: Tuning the Characteristics of Polymer Systems via Molecular Simulations
Molecular simulations are a valuable tool for sustainable polymer science since they can be employed, in conjunction with complementary experiments, to optimize the properties of polymer composites and high performance materials, thus conserving resources and reducing waste. Such an approach enables the characteristics of polymer composites and high performance materials to be predicted and tuned as a function of the chemical composition of the system as well as the conditions during processing. I will present results from a systematic study of how processing conditions during polymer extrusion can induce degradation, especially at the interface in bicomponent polymer systems; experiments validated that interfacial degradation yields a reduction in the adhesion strength and mechanical properties of the polymer fibers. We will also present the use of molecular simulations to tune the characteristics of bicomponent polymer fibers in which experiments reveal that the interface is a critical factor in the thermal actuation of shape memory.
Scott C. Blanchard, Weill Cornell Medical College
Imaging Functional Dynamics within Individual Integral Membrane Proteins Using Single-Molecule FRET
Scott Blanchard received his Ph.D. in the Program in Biophysics from Stanford University School of Medicine in 2002. There he worked under the direction of Dr. Joseph Puglisi during his thesis work focusing on the structure and function of RNA. Prior to joining the faculty at Cornell in July of 2004, he was a post-doctoral fellow in the Department of Applied Physics at Stanford University under the supervision of Dr. Steven Chu. During this period, he was able to make the first demonstrations that the ribosome and mechanism of translation were amenable to single-molecule interrogations.
Scott is an Associate Professor in the Department of Physiology and Biophysics at Weill Cornell Medicine (WCM) located within the Tri-Institutional Network that includes Memorial Sloan-Kettering Cancer Center, and The Rockefeller University on the Upper East Side of Manhattan. He currently serves as Associate Director of the Tri-Institutional PhD Program in Chemical Biology and holds a secondary appointment in the Department of Biochemistry. Research in the Blanchard laboratory focuses on examining structure-function relationships in macromolecular assemblies, including bacterial and human ribosomes as well as integral membrane proteins, using a variety of genetic, biochemical, and spectroscopic approaches. A principal focus of these investigations is to discover how regulatory factors and small-molecule agents affect the function of these essential molecular machines.
Shannon Stahl, University of Wisconsin-Madison
Selective Oxidation of Organic Molecules with Copper/Organic-Radical Catalysis
Shannon S. Stahl is a Professor of Chemistry at the University of Wisconsin-Madison. His research focus is catalysis, with an emphasis on development and mechanistic characterization of catalytic aerobic oxidation reactions for chemical synthesis. Additional efforts focus on the chemistry of molecular oxygen related to energy conversion, including fuel cells and solar energy conversion. He was an undergraduate at the University of Illinois at Urbana–Champaign, and his subsequent training took place at Caltech (Ph.D., 1997, Advisor: Prof. John E. Bercaw) and MIT (postdoc, 1997-1999; Advisor: Prof. Stephen J. Lippard), before he started his independent position in 1999.
Thursday, December 8, 2016
Miriam Freedman, Pennsylvania State University
Surfaces and Interfaces in Atmospheric Chemistry
The most uncertain aspect of our climate system is the effect of aerosol particles. Many atmospheric processes involving aerosol particles take place at surfaces and interfaces, but their structure and role is not well understood. In this talk, I will give two examples where my research group has characterized the structure and role of surfaces and interfaces in atmospheric chemistry. Specifically, we have examined submicron organic aerosol particles that undergo liquid-liquid phase separation to form an aqueous two-phase system. Surprising, we observe a size dependence of the morphology of these particles, where for some systems, large particles are phase separated and small particles are homogeneous. We have explored the origins of the size dependence and investigated its effect on cloud condensation nucleus activity. In the second part of the talk, I will explore the role of the surface of aluminosilicate clay minerals in ice nucleation. We have determined that the decrease in ice nucleation activity observed when aluminosilicate clay minerals are exposed to inorganic acids results from the presence of the reaction product rather than changes to the mineral surface. To conclude, I will comment on additional problems in which exploring the role of surfaces and interfaces can aid our understanding of atmospheric chemistry.
Miriam Freedman graduated with her BA from Swarthmore College in 2000. She received a MS in Mathematics from the University of Minnesota from 2002. She then received her PhD in Chemistry from the University of Chicago in 2008, where she worked with Prof. Steven Sibener on helium atom scattering to investigate energy transfer in supported organic thin films. Her graduate work was supported in part by an NSF graduate fellowship. After her PhD, Miriam was a NOAA Climate and Global Change Postdoctoral Fellow at the University of Colorado at Boulder with Prof. Margaret Tolbert, where she studied the optical properties of atmospheric particles. Miriam began her independent position at the Pennsylvania State University in 2010. She received an NSF CAREER award in 2014.