Department of Chemistry
Penn Chemistry is composed of a dynamic community of researchers creating and disseminating new knowledge at the forefront of the chemical sciences. As an enabling science, chemistry is at the focal point of every important modern societal challenge. Our faculty and students engage these challenges daily on a local, national, and international scale.
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Publication Reverse-Polarity Activity-Based Protein Profiling(2019-05-01) Dettling, SuzanneReverse-polarity activity-based protein profiling (RP-ABPP) is a chemical proteomics approach that uses clickable, nucleophilic hydrazine probes to capture and identify protein-bound electrophiles in cells. The RP-ABPP approach is used to characterize the structure and function of reactive electrophilic PTMs and the proteins that harbor them, which may uncover unknown or novel functions of proteins in an endogenous setting. RP-ABPP has demonstrated utility as a versatile method to monitor metabolic regulation of electrophilic cofactors, as was done with the pyruvoyl cofactor in S-adenosyl-L- methionine decarboxylase (AMD1) and discover novel types of electrophilic modifications on proteins in human cells, as was done with the glyoxylyl modification on secernin-3 (SCRN3). These cofactors cannot be predicted by sequence and as such this area is relatively undeveloped. RP-ABPP is the only global unbiased approach to discover these electrophiles. Here, the utility of these experiments is described and a detailed protocol is provided for de novo discovery, quantitation, and global profiling of electrophilic functionality of proteins through the use of nitrogenous nucleophilic probes deployed directly to living cells in culture.Publication The Influence of Alkali and Alkaline Earth Metals on Transition-metal Catalyzed Reactions(2018-05-17) Qi, JiaAlkali and alkaline earth metals are useful co-catalysts in many inorganic and organometallic reactions. The interactions of these metals to transition-metal complexes modulate the overall structures. The alkali and alkaline earth metal ions withdraw electron density from transition metal center and tune the reduction potentials. The stabilization of anion intermediates by alkali and alkaline earth metal ions reduces transition-state energy and enhance the reactivity kinetically. In homogeneous catalysis, alkali and alkaline earth metals have been shown to bind to electron-rich anionic ligands that then stabilize the formation of heterobimetallic complexes. This is especially important when key transition states are stabilized by such coordination as this can lead to greatly enhanced catalytic efficiency. These metal ions can also collaboratively bind to crown-ether installed ligands and control metal-ligand cooperativity. In addition, reaction selectivity could also be enhanced by using different sizes of alkali or alkaline earth metal ions. Thus, incorporation of alkali and alkaline earth metals to transition-metal catalysts can modulate or completely change the reactivity.Publication Influence of Growth Conditions on the Secondary Metabolite profile of Penicillium rubens Biourge(2017-05-07) Persun, Michael MThe search for antifouling compounds led us to investigate the production of the secondary metabolite meleagrin by fermentation of Penicillium rubens Biourge. Since initial growth attempts yielded none of the desired product, subsequent growth condition studies sought to enhance meleagrin production. The aim of this study was to identify conditions that selectively enhanced the production of meleagrin and other desirable secondary metabolites. This goal was accomplished by detecting, isolating and characterizing the secondary metabolites resulting from alterations to the growth media’s composition as well as the addition of a biosynthetic precursor, roquefortine C. In addition to identifying growth conditions that produce meleagrin, the present study optimized the production increase production of meleagrin by 446%, viridicatin by 237%, penitrem E by 344%, and penitrem A by 481%. This research represents the first systematic growth enhancement study for P. rubens Biourge and illustrates that slight modifications to growth conditions can have a significant impact on the production of secondary metabolite distribution and abundance.Publication Monolayer Self-Assembly of Monodisperse Nanocrystals at The Liquid-Air Interface(2020-05-05) An, DiThe study of nanocrystals (NCs) self-assembly into monolayers have attracted significant interests, due to wide applications in sensors, catalysts, nanodevices and pattern transfer. Liquid-air interface self-assembly (LAISA) is a useful technique used for the monolayer fabrication. In this capstone project, a library of NCs is built for LAISA and binary superlattice study. Monodisperse iron oxide, gold and gadolinium fluoride NCs of various sizes were synthesized by modifying reported methods.9,10,20 The obtained NCs were characterized by TEM, SAXS, DLS and TGA, revealing their geometry, size and surface chemistry. The second part of this project is optimizing conditions of LAISA. Significant variables, including evaporation rate, NCs geometry, and ambient environment were isolated and studied for different building blocks. Centimeter-scale NCs monolayers with long-range order were obtained by using optimized conditions of LAISA. The binary superlattice system of spherical NCs was also investigated during this project with optimized LAISA. A 1:2 number ratio of iron oxide to gold NCs was used to fabricate binary superlattice monolayers by LAISA. The structure was revealed with TEM. However, future work is needed to investigate other size ratio and number ratio of two different kinds of NCs, and their effects on 2D structures.Publication Using α-Helical Coiled-Coils to Design Nanostructured Metalloporphyrin Arrays(2008-09-10) McAllister, Karen A; Zou, Hongling; Cochran, Frank V; Bender, Gretchen M; Senes, Alessandro; Fry, H Christopher; Nanda, Vikas; Keenan, Patricia A; Lear, James D; Saven, Jeffery G.; Therien, Michael J; Blasie, J Kent; DeGrado, William FWe have developed a computational design strategy based on the alpha-helical coiled-coil to generate modular peptide motifs capable of assembling into metalloporphyrin arrays of varying lengths. The current study highlights the extension of a two-metalloporphyrin array to a four-metalloporphyrin array through the incorporation of a coiled-coil repeat unit. Molecular dynamics simulations demonstrate that the initial design evolves rapidly to a stable structure with a small rmsd compared to the original model. Biophysical characterization reveals elongated proteins of the desired length, correct cofactor stoichiometry, and cofactor specificity. The successful extension of the two-porphyrin array demonstrates how this methodology serves as a foundation to create linear assemblies of organized electrically and optically responsive cofactors.Publication The Study of Sulfenate and Sterically Hindered Chalcogenide Anions as Organocatalysts for the Construction of C-C Bonds(2017-08-01) Annunziato, Christopher MChalcogenides are highly redox active and biologically potent nucleophiles with significant unexplored catalytic potential. In particular, sulfenate anions potential as organocatalyst has largely been overlooked in the literature due to their esoteric status. A unique sulfenate anion catalyzed Baylis Hillman (BH) reaction forming sp2-sp3 C-C bonds is in development. In this two-part study, part one focuses on screening conditions suitable for both cleavage of a precatalyst and subsequent BH reaction. Whereas part two focuses on the proclivity of chalcogenide oxyanions to disproportionate. Sterically hindered analogs were investigated, to prevent catalyst decomposition. The sulfenate anion catalyzed (20 mol %) BH reaction was conducted in the presence of α,β-unsaturated nitriles, ketones and esters to generate allylic alcohols in yields up to 37%. Precatalyst cleavage studies were an integral part to the realization of smooth sulfenate anion generation. Efforts to optimize the BH reaction conditions are ongoing.Publication Employing Confidence Intervals in Electron Microscopy Digital Image Analysis to Promote Better Analytical Practices(2021-05-01) Arndt, Diana sAs the range of applications for nanoparticle systems continues to expand, the importance of providing reliable, informative, quantitative characterization for nanomaterial categorization and quality control continues to increase. Transmission Electron Microscopy (TEM) is a standard characterization technique that provides nanoscale image representations of a thin nanomaterial sample and has the potential to provide quantitative information with substantial digital image analysis. Modern semi-automatic TEM image analysis processes, such as the popular software ImageJ, aim to improve on outdated manual processes by incorporating user input with automated algorithms, decreasing the potential for human error and time expense. These processes segregate particles from the background in grayscale TEM images based on pixel intensity or particle shape, then calculate attributes such as size parameters from the derived shapes. However, in attempting to create processes that require little effort and time for the user, current image analysis procedures often undervalue the user’s knowledge of the system. Because the automated algorithms are expected to incorporate information about the system more suited to human determination, particles are often misidentified, resulting in inaccurate calculations. Furthermore, the automated algorithms are hidden from the user, making discussion of data manipulation biases arduous. To address these limitations, a novel TEM image analysis process was developed by integrating a traditional data analytics perspective. To provide feedback on the reliability of quantified size parameters, the presented process introduces confidence intervals based on image contrast and noise. These percentages represent the clarity of the image and variability between particles, allowing the user to choose what areas of the image they want to include in analysis. Encompassed in an easy-to-use MATLAB® App dashboard, the process allows the user to customize a more effective TEM image analysis process based on confidence interval feedback. In this project, a GdF3:Yb/Er rhombus nanoplatelet system and two Fe3O4 spherical systems were analyzed with the MATLAB® App to quantify size parameters comparable to standard ImageJ analysis. Additionally, the application’s ability to reveal image properties using confidence intervals is showcased by probing the effects of pre-processing regimes, magnification variation, and shape matching on size parameter reliability.Publication Synthesis of Au-Ag Alloy Nanoparticles and Characterization of Nanoparticle-Anthracene Hybrid Materials(2020-01-01) ZHOU, XIANGIn this work, the optical properties of Au-Ag alloys with an anthracene ligand grafter to their surfaces was examined. Structurally and chemically homogeneous Au-Ag alloy NPs were synthesized by a seed-mediated method with the Ag precursor reduced and grown onto the prepared Au seeds. The alloy NPs were formed after inter-diffusion of Au and Ag and protected using oleylamine. Functionalization of the metal NPs with the anthracene-incorporated ligands was conducted via a simple ligand exchange protocol. The morphological information and chemical composition of the resulting NPs were confirmed by transmission electron microscopy and energy dispersive X-ray spectroscopy, respectively. The plasmonic effect of the metal NPs on the fluorescence was examined using Ultraviolet-visible and fluorescence spectroscopy. The plasmonic enhancement of the fluorescence was found to be varied among different compositions of the alloy NPs.Publication Synthesis and Biological Evaluation of Biliatresone Analogs and its Photoaffinity Probe(2019-07-25) Lin, ShengPublication NMR Structure and Dynamics of a Designed Water-Soluble Transmembrane Domain of Nicotinic Acetylcholine Receptor(2012-03-01) Cui, Tanxing; Mowrey, David; Bondarenko, Vasyl; Tillman, Tommy; Ma, Dejian; Landrum, Elizabeth; Perez Aguilar, Jose Manuel; He, Jing; Wang, Wei; Saven, Jeffery G.; Eckenhoff, Roderic G; Tang, Pei; Xu, YanThe nicotinic acetylcholine receptor (nAChR) is an important therapeutic target for a wide range of pathophysiological conditions, for which rational drug designs often require receptor structures at atomic resolution. Recent proof-of-concept studies demonstrated a water-solubilization approach to structure determination of membrane proteins by NMR (Slovic et al., PNAS, 101: 1828–1833, 2004; Ma et al., PNAS, 105: 16537–42, 2008). We report here the computational design and experimental characterization of WSA, a water-soluble protein with ~ 83% sequence identity to the transmembrane (TM) domain of the nAChR α1 subunit. Although the design was based on a low-resolution structural template, the resulting high-resolution NMR structure agrees remarkably well with the recent crystal structure of the TM domains of the bacterial Gloeobacter violaceuspentameric ligand-gated ion channel (GLIC), demonstrating the robustness and general applicability of the approach. NMR T2 dispersion measurements showed that the TM2 domain of the designed protein was dynamic, undergoing conformational exchange on the NMR timescale. Photoaffinity labeling with isoflurane and propofol photolabels identified a common binding site in the immediate proximity of the anesthetic binding site found in the crystal structure of the anesthetic-GLIC complex. Our results illustrate the usefulness of high-resolution NMR analyses of water-solubilized channel proteins for the discovery of potential drug binding sites.