Abstract: The presenter's Ph.D. in chemistry (chemical biology path) focused on harnessing peptide chemistry with structural and biophysical approaches to uncover how subtle changes in peptide architecture can be used to reshape GPCR signaling and immune signaling in useful ways. 

For his postdoctoral work, he turned his focus to proteostasis by pursuing biological characterization of small-molecule activators of autophagy discovered via a high-throughput, imaging-based screen. This public seminar will highlight some of these research findings. In his future independent lab, Russ seeks to scrutinize and therapeutically harness GPCR and kinase networks to address novel questions at the interface of chemical biology, signal transduction and drug discovery.

Abstract: The presenter's Ph.D. in chemistry (chemical biology path) focused on harnessing peptide chemistry with structural and biophysical approaches to uncover how subtle changes in peptide architecture can be used to reshape GPCR signaling and immune signaling in useful ways. 

For his postdoctoral work, he turned his focus to proteostasis by pursuing biological characterization of small-molecule activators of autophagy discovered via a high-throughput, imaging-based screen. This public seminar will highlight some of these research findings. In his future independent lab, Russ seeks to scrutinize and therapeutically harness GPCR and kinase networks to address novel questions at the interface of chemical biology, signal transduction and drug discovery.

Small molecules that induce protein interactions hold tremendous potential as new medicines, as probes for molecular pathways and as tools for agriculture. Explosive growth of targeted protein degradation drug development has spurred renewed interest in proximity inducing molecules and especially molecular glue degraders. These compounds catalyze destruction of disease-causing proteins by reshaping protein surfaces and promoting cooperative binding between ubiquitylating enzymes and target proteins. 

Molecular glue discovery for pre-defined targets is a major challenge in contemporary drug discovery. Here I will discuss how we address these chemical challenges through molecular glue discovery enabled by targeted degron display. By leveraging mechanisms such as electrophilic covalent bonding, electrostatic interactions, or cation-pi interactions, I have identified a range of potent molecular glue degraders that recruit previously unligandable ubiquitylating factors for multiple therapeutically relevant epigenetic regulators and kinases. This "chemocentric" approach provides a powerful strategy to discover molecular glues that induce proximity to ubiquitin ligases with similarly desirable properties. 

Small molecules that induce protein interactions hold tremendous potential as new medicines, as probes for molecular pathways and as tools for agriculture. Explosive growth of targeted protein degradation drug development has spurred renewed interest in proximity inducing molecules and especially molecular glue degraders. These compounds catalyze destruction of disease-causing proteins by reshaping protein surfaces and promoting cooperative binding between ubiquitylating enzymes and target proteins. 

Molecular glue discovery for pre-defined targets is a major challenge in contemporary drug discovery. Here I will discuss how we address these chemical challenges through molecular glue discovery enabled by targeted degron display. By leveraging mechanisms such as electrophilic covalent bonding, electrostatic interactions, or cation-pi interactions, I have identified a range of potent molecular glue degraders that recruit previously unligandable ubiquitylating factors for multiple therapeutically relevant epigenetic regulators and kinases. This "chemocentric" approach provides a powerful strategy to discover molecular glues that induce proximity to ubiquitin ligases with similarly desirable properties. 

Compared to ubiquitous functional groups such as alcohols, carboxylic acids, amines and amides, which serve as central “actors” in most organic reactions, sulfamates, phosphoramidates and di-tert-butyl silanols have historically been viewed as “extras."

Largely considered functional group curiosities rather than launchpoints of vital reactivity, the chemistry of these moieties is underdeveloped. Our research program has uncovered facets of reactivity of each of these functional groups, and we are optimistic that the chemistry of these fascinating molecules can be developed into general transformations useful for chemists across multiple disciplines. In the ensuing sections, I will describe our efforts to develop new reactions with these “unusual” functional groups, namely sulfamates, phosphoramidates, and di-tert-butyl silanols.

Compared to ubiquitous functional groups such as alcohols, carboxylic acids, amines and amides, which serve as central “actors” in most organic reactions, sulfamates, phosphoramidates and di-tert-butyl silanols have historically been viewed as “extras."

Largely considered functional group curiosities rather than launchpoints of vital reactivity, the chemistry of these moieties is underdeveloped. Our research program has uncovered facets of reactivity of each of these functional groups, and we are optimistic that the chemistry of these fascinating molecules can be developed into general transformations useful for chemists across multiple disciplines. In the ensuing sections, I will describe our efforts to develop new reactions with these “unusual” functional groups, namely sulfamates, phosphoramidates, and di-tert-butyl silanols.

Abstract: The physicochemical properties of aerosols and droplets, including phase state, pH and viscosity, impact processes from respiratory virus transmission to critical atmospheric processes to recent reports of incredible accelerations in chemical reactivity in microdroplets. Yet, these properties are challenging to measure directly in situ due to the small sizes and sensitive nature of the particles. Here, the use of fluorescence probe spectroscopy as a versatile tool for measuring these critical properties in situ in submicron aerosols is presented, along with a discussion of how the measured properties differ or not from those of larger particles or bulk phases, with implications for each of the aforementioned application areas.

Abstract: Conjugated polymers continue to emerge as next-generation electronic materials for mixed ionic-electronic conduction applications ranging from biomedical sensing to energy storage. Their development, however, is hampered by a lack of rational design principles due to missing fundamental knowledge about how ion-charge interactions and dynamic polymer nanostructure influence charge transport and storage along polymer chains.

In this talk, I will first discuss how we are exploiting the ultrafast dynamics of photoexcited charge carriers to provide details on their nanoscale environment and trapping behavior. Then I will show how in situ electronic and vibrational spectroscopy of polymer electrodes can be used to track their complex nanoscale dynamics during charging, revealing insights into nanostructures that support the formation of mobile carriers.

Abstract: Soluble methane monooxygenase (sMMO) catalyzes the cleavage of the strong C-H bond of methane during the O₂-dependent conversion to methanol. sMMO generates nature’s most powerful oxidizing agent, a Fe₂-(mu-oxo)₂ species termed Q, for this reaction. The sMMO catalytic cycle is strictly regulated to ensure that methane is afforded preferential access to Q, as Q is capable of oxidizing any molecule with a C-H or C=C bond that gains access to the active site. 

This methane selection process is ascribed to a small-molecule tunnel to the active site that discriminates based upon the molecular size of the substrate. The experimental validation of this regulatory model is held back by the inability to mutate the hydroxylase protein (MMOH), which harbors the active site, in a site-specific manner. We have overcome this obstacle by recombinantly expressing MMOH in E.coli through co-expression with two other proteins, MMOG and MMOD, from the sMMO operon. 

This effect results in a large yield of a fully functional MMOH protein for sMMO structure-function studies. The tools used to enable this breakthrough are broadly applicable and benefit the soluble production of other enzymes. A vignette will also be provided of our investigation into strong N-H cleavage chemistry based upon the promiscuous conversion of ammonia to hydroxylamine by sMMO. 

Bio: My love for enzymology was fostered during my doctoral studies in John D. Lipscomb’s laboratory at the University of Minnesota-Twin Cities. This research was focused on investigating the chemical mechanism of the soluble methane monooxygenase (sMMO) enzyme, which catalyzes the oxygen dependent oxidation of methane to methanol as part of methanotroph C1 metabolism. I came to appreciate how enzymes are masterful in catalyzing challenging chemical conversions.

I also learned an important lesson here that biochemical studies are only as good as the enzyme that is purified (homogeneous, highly-active preparations). This was a hard lesson to learn as I found myself in the fifth year of a Ph.D. with no positive results to report. I hope that my journey in science shows graduate students who are struggling with challenging research projects that their research is just a few good ideas and experiments away from giving up its secrets. 

Close to the end of my doctoral research, I had gotten involved in a continuous-flow resonance Raman study of the photolabile, methane reactive intermediate in sMMO. Since this was a brute-force experiment that consumed thirty grams of purified protein, I decided to continue my sMMO research as a post-doctoral scholar in the same laboratory to ensure its success. 

During this post-doctoral research, I broadened my research training through a focus upon elucidating the mechanisms of catalytic regulation enforced by the protein structure and protein-protein interactions. These regulatory schemes ensure that methane is chosen as the native substrate (sMMO will oxidize any organic compound that enters its active site) and that high-valent iron intermediates are not aberrantly quenched by mis-timed electron transfer from an accessory reductase protein. 

This period of my research training taught me that in as much as the high-valent metal-oxygen intermediates capture the limelight, it is these mechanisms of regulation that truly showcase the catalytic prowess of enzymes. These two facets of catalysis, namely chemical reactivity and its regulation, are the focus of research in my laboratory. The two model systems under study include the sMMO enzyme and the integral membrane stearoyl-CoA desaturase (SCD) enzyme, which catalyzes the desaturation of fatty acids in eukaryotes. 

Both these enzymes utilize dinuclear iron cofactors to activate oxygen and generate powerful oxidants in order to functionalize strong C-H bonds, while preventing oxidative damage from reactive oxygen species resulting from uncoupled enzyme turnovers. The goal of this research is to inform synthetic catalyst design for strong C-H bond functionalization chemistry and to elucidate the general tenets of enzyme action.

Functional materials used for optoelectronic applications are often employed in the solid-state regime. The properties of such solid-state materials are entirely dependent on the inter and intra molecular interactions that the molecules experience. Intermolecular interactions are interactions between two adjacent molecules and can be broken down into two subgroups: repulsive and attractive. Intramolecular interactions are interactions that occur within a molecule and include things like bonding, resonance, and electron distribution. These properties can be tuned through a number of techniques to afford desirable outcomes for various material applications. This dissertation will investigate how the tuning of the inter and intra molecular forces influence a material’s electronic and optical properties.

The dissertation will cover three projects that leverage control over hydrogen bonding, ionic interactions, and electron density to influence the optoelectronic properties of various systems. The first project attempted to increase intermolecular electronic couplings by using hydrogen bonded coproducts between an organic small molecule semiconductor and benzoic acids. Hydrogen bonding is a monodirectional interaction. The second project, in contrast, focuses on ionic interactions, which are multidirectional. These ionic interactions were investigated through the addition of a conjugated organic core to the inorganic anion in an organic inorganic hybrid material (OIHM) to improve material photoluminescence quantum yield (QY) efficiency. Additionally, alkyl substituents and anion size were changed to probe the effect of spacing on QY. In the third project of this dissertation, the focus moves from intermolecular interactions to intramolecular interactions. This project focuses on using electron donating and accepting groups to tune the highest occupied molecular orbital (HOMO) and lowest unoccupied molecular orbital (LUMO) levels of a metal complex to achieve more efficient deep red and near infrared (NIR) emission.

KEYWORDS: Intermolecular Interactions, Intramolecular Interactions, Optoelectronics, Organic Semiconductors, Light Emitting Materials