Seminars Archive

Folding- and dynamics-based electrochemical biosensors

Professor Rebecca Lai | University of Nebraska-Lincoln

Professor Jill Venton

This seminar will cover the recent advances in the design and fabrication of folding- and dynamics-based electrochemical biosensors. These devices, which are often termed electrochemical DNA (E-DNA), aptamer-based (E-AB), and peptide-based (E-PB) sensors, are fabricated via direct immobilization of a thiolated and methylene blue (MB)-modified oligonucleotide or peptide probe onto a gold electrode. Binding of an analyte to the probe changes its structure and/or flexibility, which, in turn, influences the electron transfer between the MB label and the interrogating electrode. These sensors are resistant to false positive signals arising from the non-specific adsorption of contaminants and perform well even when employed directly in whole blood, saliva, and other realistically complex sample matrices. Furthermore, because all of the sensing components are chemisorbed onto the electrode surface, they are readily regenerable and reusable. Our results show that many of these sensors have achieved state-of-the-art sensitivity while offering the unprecedented selectivity, reusability and operational convenience of direct electrochemical detection.

In silico searches for (in)efficient electrocatalysts through chemical and material compound space

Professor John Keith | University of Pittsburgh

Professor Charlie Machan

This talk will provide an overview of our group’s work using both standard and atypical high-performance computational chemistry modeling to elucidate atomic scale reaction mechanisms of catalytic reactions. I will introduce our toolkit of in silico methods for accurately modeling (electro)catalytic reactions in solvating environments. I will then present how in silico methods can be used for predictive insights into chemical and material design. The talk will then highlight our progress in modeling 1) the complex Morita-Baylis-Hillman reaction, 2) inefficient amorphous TiO2 materials as anti-corrosion coatings, and 3) biomimetic CO2 reduction mechanisms.

Quantifying biochemistry in living cells

Professor Amy Palmer | University of Colorado at Boulder

Professor Andreas Gahlmann

Increasingly, fluorescent tools are providing insight into the “dark matter” of the cellular milieu: small molecules, secondary metabolites, metals, and ions.  One of the great promises of such tools is the ability to quantify cellular signals in precise locations with high temporal resolution.  Yet this is coupled with the challenge of how to ensure that our tools are not perturbing the underlying biology and the need to systematically measure hundreds of individual cells over time.  The focus of research in the Palmer Lab is to develop fluorescent tools to illuminate and quantify biochemistry in living cells.  In addition to developing such tools, we strive to develop robust systematic analytical approaches for using sensors and fluorescence microscopy to carry out quantitative biochemistry at the single cell level.  Over the past 12 years our greatest effort has been in understanding the cell biology of zinc.  We have developed fluorescent sensors to map out the spatial distribution of zinc ions and quantify zinc dynamics in live mammalian cells.  These tools have allowed us to answer fundamental questions such as: where zinc is located in cells, how much is present in different kinds of cells, under what conditions zinc ions are dynamic, and how the zinc status of healthy cells differs from diseased cells.  Along the way, we have also established benchmark analytical approaches for using fluorescent sensors for quantitative biology and biophysics.  We have developed microfluidic cell sorting technologies to study and engineer fluorescent tools.  We have leveraged our expertise in fluorescent probes, single cell biology and live cell imaging to establish new methods for defining the complex dynamic interface between bacterial pathogens and host mammalian cells. And finally, we have started to expand our reach to develop chemical biology tools for labelling and tracking RNA in live cells.  This talk will provide a highlight of these research areas.

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From basic chemistry to new opioid biology

Professor Jeff Aube | University of North Carolina, Chapel Hill

Professors Ken Hsu and John Lazo

The worldwide opioid crisis has occasioned efforts to develop new opioids for both existing uses (pain control) as well as new indications (itch, addiction). We have focused on the discovery of compounds able to selectively activate one of the two main intracellular pathways associated with the kappa opioid receptor. This type of activity, called “functional selectivity” or “ligand bias”, has the potential to segregate many of the ultimate biological effects of therapeutic opioids.

This project is an effort of a multidisciplinary, multi-institutional team led by the speaker and Professor Laura Bohn of the Scripps Research Institute.[1,2] It began with the development of a speculative library for screening against a range of potential biological targets based on a known but underexplored isoquinolinone synthesis. Applying this chemistry to library synthesis led to a hit compound that stoked our interest in biased ligand discovery, ultimately leading to the discovery of Triazole 1.1, a strongly biased KOR agonist with a fascinating in vitro and in vivo profile. These efforts and recent results will be described.

[1] Bohn, L.M.; Aubé, J. ACS Med. Chem. Lett, 2017, 8, 694–700.

[2] Brust, T. F.; Morgenweck, J.; Kim, S. A.; Rose, J. H.; Locke, J. L.; Schmid, C. L.; Zhou, L.; Stahl, E. L.; Cameron, M. D.; Scarry, S. M.; Aubé, J.; Jones, S. R.; Martin, T. J.; Bohn, L. M. Biased Agonists of the Kappa Opioid Receptor Suppress Pain and Itch Without Causing Sedation or Dysphoria. Sci. Signal. 2016, 9, ra117.

Jeffrey Aubé attended the University of Miami, where he did undergraduate research with Professor Robert Gawley (with whom he later co-authored the graduate text “Principles of Asymmetric Synthesis”, currently in its second edition). He received his Ph.D. in chemistry in 1984 from Duke University, working with Professor Steven Baldwin, and was an NIH postdoctoral fellow at Yale University with Professor Samuel Danishefsky. From 1986 until 2015, he held a faculty position in the Department of Medicinal Chemistry at the University of Kansas. In 2015, he retired from KU and moved to the University of North Carolina, where he is an Eshelman Distinguished Professor in the Division of Chemical Biology and Medicinal Chemistry. In addition to holding a joint appointment in the Department of Chemistry, Aubé is a member of the Center for Integrative Chemical Biology and Drug Discovery and the Lineberger Cancer Center.

Aubé’s research interests lie in the chemistry of heterocyclic compounds and their applications to problems in medicinal organic chemistry. The lab’s interests in bioorganic chemistry include collaborations in the area of opioid pharmacology (with Laura Bohn), steroid biosynthesis inhibitors (with Emily Scott), and in the discovery of anti-Mtb agents (with Carl Nathan). Aubé served as the principal investigator of the Chemical Methodology and Library Development Center program at Kansas as well as a specialized chemistry lab in the NIH’s Molecular Libraries Initiative.

Aubé has been honored for his research and scholarship by his receipt of awards from the American Chemical Society (including the Arthur C. Cope Scholar Award and the Midwest Award, bestowed by the St. Louis Section of the ACS) and for teaching (including the university-wide HOPE Award and the Kemper Fellowship for Teaching Excellence at KU). He is a fellow of both the American Association for the Advancement of Science and the American Chemical Society.

Redefining druggability using chemoproteomic platforms

Professor Dan Nomura | University of California, Berkeley

Professor Ken Hsu

Once upon a time in Kamchatka: The extraordinary search for natural quasicrystals

Professor Paul Steinhardt | Princeton University |

Professors Kateri DuBay and Jill Venton

Activity assisted self-assembly of colloidal particles

Professor Angelo Cacciuto | Columbia University |

Professor Kateri DuBay

New recipes for biocatalysis: Expanding the cytochrome P450 chemical landscape

Professor Eric Brustad | University of North Carolina, Chapel Hill

Professor Ken Hsu

The design and engineering of protein catalysts that carry out rare or non-natural chemistry remains a challenging contemporary goal. However, enzymes are inherently limited by their chemical composition, i.e. the reagent pool that exists in nature and the amino acids and cofactors that form their physical and catalytic core. Because of this limitation, the majority of chemical transformations developed by synthetic chemists remain, at least to our knowledge, biologically inaccessible. Biological cofactors and prosthetic groups, including heme, provide a convenient means for natural proteins to increase their range of chemical transformations. Synthetic catalysts, similar to heme, demonstrate a wealth of chemical transformations, including metallocarbene insertion reactions, through mechanisms similar to native P450 catalysis; however, these reactions do not exist in biology due to the lack of the necessary ingredients in the cell or surrounding environment. By supplementing cytochrome P450s with non-natural reagents we have been able to demonstrate that a variety of natural enzyme scaffolds are capable of carrying out reactions, including the carbene-mediated cyclopropanation of olefins, not previously observed in the natural world. Moreover, as adaptable, genetically encoded systems, the activity and product regio- and stereochemical profiles of these catalysts can be tuned through mutation. We have shown that this non-natural chemistry can be applied for fine chemical synthesis, or even adapted to modify native P450 substrates. We have gone on to show that cytochrome P450s can be evolved for the incorporation of alternative metalloporphyrin scaffolds. By combining non-natural cofactor engineering with an increase in reagent diversity, we are generating orthogonal protein systems that deliver function not available to heme containing proteins.

Eric Brustad is a proud native of Indianapolis, Indiana. He graduated from Purdue University (W. Lafayette, IN) in 2002 receiving B.S. degrees in Chemistry and Biology as well as a B.A. in French. As an undergraduate, he began his research career in bioorganic chemistry under the mentorship of Jean Chmielewski. In the fall of 2002, he joined The Scripps Research Institute to carry out graduate research under the direction of Peter G. Schultz. His thesis work examined applications of unnatural amino acid mutagenesis to expand protein function. Dr. Brustad moved to the California Institute of Technology in December of 2008 as a Ruth Kirschstein postdoctoral fellow where he joined the group of Frances H. Arnold. While at Caltech, Dr. Brustad applied directed protein evolution to engineer proteins for non-natural catalysis or biosensing applications. In 2012, Eric joined the Department of Chemistry and the Carolina Center for Genome Sciences at the University of North Carolina at Chapel Hill. His research program focuses on combining chemical, biological and evolutionary approaches to expand the capabilities of living cells.  His honors include the Barry M. Goldwater Scholarship (2002), a Ruth L. Kirschstein National Research Service Award (2009), a DARPA Young Faculty Award (2013), and an NSF Career Award (2015).

Searching for selective catalytic reactions in complex molecular environments

Professor Scott Miller | Yale University

Professor Mike Hilinski

This lecture will describe recent developments in our efforts to develop low-molecular weight catalysts for asymmetric reactions.  Over time, our view of asymmetry has ebbed and flowed, with foci on enantioselectivity, site-selectivity and chemoselectivity.  In most of our current work, we are studying issues of enantioselectivity as a prelude to extrapolation of catalysis concepts to more complex stereochemical settings where multiple issues are presented in a singular substrate.  Moreover, we continuously examine an interplay between screening of catalyst libraries and more hypothesis-driven experiments that emerge from screening results.  Some of the mechanistic paradigms, and their associated ambiguities, will figure strongly in the lecture.

Scott J. Miller was born on December 11, 1966 in Buffalo, NY. He received his B.A. (1989), M.A. (1989) and Ph.D. (1994) from Harvard University, where he worked with David Evans as a National Science Foundation Predoctoral Fellow.  Subsequently, he traveled to the California Institute of Technology where he was a National Science Foundation Postdoctoral Fellow with Robert Grubbs until 1996. For the following decade, he was a member of the faculty at Boston College, until joining the faculty at Yale University in 2006.  In 2008, he was appointed as the Irénée duPont Professor of Chemistry.

Professor Miller’s research program focuses on catalysis. His group employs strategies that include catalyst design, the development of techniques for catalyst screening, and the application of new catalysts to the preparation of biologically active agents.  Three current interests are (a) the selective functionalization of complex molecules, (b) the exploration of analogies between synthetic catalysts and enzymes and (c) the discovery of effective antibiotics despite increasing resistance.

Scott Miller’s awards and honors include: National Science Foundation CAREER Award (1999), Alfred P. Sloan Research Fellowship (2000), Camille Dreyfus Teacher-Scholar Award (2000), Arthur C. Cope Scholar Award of the American Chemical Society (2004), Yoshimasa Hirata Memorial Gold Medal of Nagoya University (2009), National Institutes of Health MERIT Award (2011), Fellow of the American Association for the Advancement of Science (2012), American Chemical Society Award for Creative Work in Synthetic Organic Chemistry (2016), Member, American Academy of Arts and Sciences (2016), Max Tishler Prize, Harvard University (2017).

Professor Miller has served in number of capacities for public and private organizations.  For example, he recently completed a term on the National Institute of General Medical Sciences Advisory Council, convened by the Director of the National Institutes of Health.  He now serves as Editor-in-Chief of The Journal of Organic Chemistry.