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
    Computational Design of Water-Soluble Analogues of the Potassium Channel KcsA
    (2004-02-17) Lear, James D; Slovic, Avram Michael; Saven, Jeffery G.; Kono, Hidetoshi; DeGrado, William F
    Although the interiors of membrane and water-soluble proteins are similar in their physicochemical properties, membrane proteins differ in having larger fractions of hydrophobic residues on their exteriors. Thus, it should be possible to water-solubilize membrane proteins by mutating their lipid-contacting side chains to more polar groups. Here, a computational approach was used to generate water-soluble variants of the potassium channel KcsA. As a probe of the correctness of the fold, the proteins contain an agitoxin2 binding site from a mammalian homologue of the channel. The resulting proteins express in high yield inEscherichia coli and share the intended functional and structural properties with KcsA, including secondary structure, tetrameric quaternary structure, and tight specific binding to both agitoxin2 and a small molecule channel blocker.
  • Publication
    Molecular Analysis of Copper Binding to the Bacterial MFS-type Copper Importer CcoA
    (2019-05-15) Zhao, Wenchu
    Many enzymes require copper (Cu) as a cofactor in proceeding their role in different biological pathways. Copper’s oxidative and reductive abilities make it a good cofactor to accomplish the electron transfer process in reactions. CcoA was discovered in the Gram-negative, facultative photosynthetic model organism Rhodobacater capsulatus. It was found to belong to the Major Facilitator Superfamily (MFS) group of transporter proteins and since then had become the prototype of the newly defined copper uptake porter family. In this capstone project, an antibody that specifically targets the CcoA protein was screened in order to contribute to future molecular analysis of copper binding of the CcoA in the Rhodobacater capsulatus. Different antibody and sample preparation methods were tested in order to optimize the western blot recognition results. Additionally, in order to further investigate the function of the conserved residues in CcoA-like-Transporter family, another aim of the study was focused on the study of the activity of the ccb3-type cytochrome oxidases in a mutant lacking the CcoA homolog protein of the Agrobacterium tumefaciens (fabrum). The study gives insights to the Cu uptake and delivery pathways of the CcoA-like-Transporter in a different bacterial species, and the role of this oxidase on tumor formation in plants. It also emphasizes the function of the conserved histidine residue in these transporters.
  • Publication
  • Publication
    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; Perez Aguilar, Jose Manuel; Landrum, Elizabeth; He, Jing; Saven, Jeffery G.; Wang, Wei; Eckenhoff, Roderic G; Tang, Pei; Xu, Yan
    The 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.
  • Publication
    Oxidative Coupling of Phenols
    (2018-05-19) Sreevatsan, Prasanna
    Nature makes extensive use of oxidative reactions to generate bonds between carbons, particularly in the coupling of phenols, which is a striking feature in many biosynthetic pathways. The coupled phenols may exhibit the phenomenon called axial “chirality” or handedness. The Kozlowski group uses the atom economical oxidant O2 and metal-based catalysts which, developed in-house, mimic the active sites of the enzymes to bring about these transformations. Vanadium catalysts have been extensively applied to the coupling of phenols and carbazoles with great efficiency and results. Here, this method is applied to the synthesis of bismurrayaquinone-A, an antitumor compound that occurs naturally in the roots of the curryleaf tree, Murraya koenigii. In this report, the routes for synthesis of the coupled phenol and carbazoles are highlighted. In the scaleup synthesis, 515 mg of the coupled carbazole was synthesized with an overall of 68% yield and 91% ee. A key oxidative coupling intermediate in the synthesis of bismurrayaquinone-A was afforded in 51% ee.
  • Publication
    Synthesis and Optical Properties of Rare Earth Doped Fluorides Nanoparticles Via Enhanced Absorption
    (2019-05-19) Wu, Yupeng
    Rare-earth elements are strong candidates for upconverting materials due to their relatively long-lived excited states.1-3 However, they are generally not efficient light absorbers.4-6 One of the approaches to enhance the optical absorption is adding a sensitizer layer (i.e.an extra semiconductor layer or using organic dyes as sensitizer with stronger absorption properties).7 On the other hand, the surface quenching effect decreases the efficiency of optical emission. This project explores the creation of undoped shells, sensitizer shells on rare earth nanoparticles and studies the effect of the size of the shell, semiconductor shells and dyes on the optical properties.NaYF4:Yb0.20, Er0.02 nanoparticlesare investigated specifically to reveal the effect of sensitizers on the absorption and emission properties. A solvothermal method is used to synthesize core NaYF4:Yb0.20, Er0.02 nanoparticles and NaYF4doped core-undoped shell particles.8-13 XRD and TEM indicated that pure β-NaYF4nanoparticles were synthesized. The size of NaYF4nanoparticles was monitored using reaction time. The emission spectrum revealed that growth of undoped NaYF4shells enhanced the emission intensity of doped core-undoped shell particles. This is presumably because the shell inhibits the nonradiative transition and the surface quenching on the surface ofNaYF4:Yb0.20, Er0.02core nanoparticles. CdS shells and ligand exchange with a dye absorbing in NIR were investigated as potential methods to enhance the absorption properties of NaYF4:Yb0.20, Er0.02 nanoparticles. TEM revealed that CdS segregated to form heterostructurewith NaYF4:Yb0.20, Er0.02 core nanoparticlesinstead of core-shell structure. This is likely due to the mismatch of CdS lattice to β-NaYF4.A NIR absorbing dye was coated to the NaYF4:Yb0.20, Er0.02 corenanoparticles via ligand exchange method. A color change was noticed after the ligand exchange with the nanoparticles. However, the emission properties and energy transfer process need further studies since the intensity at 542 nm and 660 nm are not pronounced under 806 nm excitation and 980 nm excitation.
  • Publication
    Synthesis of Au-Ag Alloy Nanoparticles and Characterization of Nanoparticle-Anthracene Hybrid Materials
    (2020-01-01) ZHOU, XIANG
    In 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 photochemical studies of two p-hydroxyphenacyl derived photocages
    (2020-05-01) Deng, Changfeng
    The synthesis of new p-hydroxyphenylacyl(pHP) derived photocages containing either coumarin or benzothiazole fluorophore cores is described. The newly synthesized photocages exhibit absorption spectra extending beyond 400 nm and good photolysis efficiency. The pHP inspired design, with the insertion of a carbonyl group, provides a 50-60 nm bathochromic shift and efficient photo-cleavage. Caged chemical probes for controlled protein dimerization were prepared containing the newly developed pHP photocages. In vitro experiments verified efficient photochemical uncaging of the newly developed pHP chemical probes. Cell imaging experiments utilizing the new pHP caged probes are currently in progress.
  • Publication
    De Novo Design of a Single Chain Diphenylporphyrin Metalloprotein
    (2007-09-05) Bender, Gretchen M; Lehmann, Andreas; Zou, Hongling; Cheng, Hong; Fry, H Christopher; Engel, Don; Therien, Michael J; Blasie, J Kent; Saven, Jeffery G.; Roder, Heinrich; DeGrado, William F
    We describe the computational design of a single-chain four-helix bundle that noncovalently self-assembles with fully synthetic non-natural porphyrin cofactors. With this strategy, both the electronic structure of the cofactor as well as its protein environment may be varied to explore and modulate the functional and photophysical properties of the assembly. Solution characterization (NMR, UV-vis) of the protein showed that it bound with high specificity to the desired cofactors, suggesting that a uniquely structured protein and well-defined site had indeed been created. This provides a genetically expressed single-chain protein scaffold that will allow highly facile, flexible, and asymmetric variations to enable selective incorporation of different cofactors, surface-immobilization, and introduction of spectroscopic probes.
  • Publication
    Knowledge-Based Potential for Positioning Membrane-Associated Structures and Assessing Residue-Specific Energetic Contributions
    (2012-05-09) Hannigan, Brett Thomas; Schramm, Chaim A; Saven, Jeffery G.; Donald, Jason E; DeGrado, William F; Keasar, Chen; Samish, Ilan
    The complex hydrophobic and hydrophilic milieus of membrane-associated proteins pose experimental and theoretical challenges to their understanding. Here we produce a non-redundant database to compute knowledge-based asymmetric cross-membrane potentials from the per-residue distributions of Cβ, Cγ and functional group atoms. We predict transmembrane and peripherally associated regions from genomic sequence and position peptides and protein structures relative to the bilayer (available at http://www.degradolab.org/ez). The pseudo-energy topological landscapes underscore positional stability and functional mechanisms demonstrated here for antimicrobial peptides, transmembrane proteins, and viral fusion proteins. Moreover, experimental effects of point mutations on the relative ratio changes of dual-topology proteins are quantitatively reproduced. The functional group potential and the membrane-exposed residues display the largest energetic changes enabling to detect native-like structures from decoys. Hence, focusing on the uniqueness of membrane-associated proteins and peptides, we quantitatively parameterize their cross-membrane propensity thus facilitating structural refinement, characterization, prediction and design.