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Item Organic Photoredox Catalyzed Direct Hydroamination of Ynamides with Azoles(Wiley, 2022-03-15) Wang, Ban; Mccabe, Gavin E.; Parrish, Mitchell J.; Singh, Jujhar; Zeller, Matthias; Deng, Yongming; Chemistry and Chemical Biology, School of ScienceDisclosed herein is a photoinduced selective hydroamination of ynamides with nitrogen heteroaromatic nucleophiles. By using an organocatalytic photoredox system, a direct method to construct a diverse of (Z)-α-azole enamides from ynamides and pyrazoles, as well as triazoles, benzotriazoles, indazoles, and tetrazoles, is developed, thus providing a photocatalytically synthetic route to heterocyclic motifs common in medicinal agents. Based on the mechanistic studies, the hydroamination is postulated to operate via a mechanism in which the single-electron oxidation of ynamide and the intermediacy of an alkyne radical cation, is responsible for the observed reactivity.Item Multi-Institution Research and Education Collaboration Identifies New Antimicrobial Compounds(American Chemical Society, 2020-12-18) Fuller, Amelia A.; Dounay, Amy B.; Schirch, Douglas; Rivera, Daniel G.; Hansford, Karl A.; Elliott, Alysha G.; Zuegg, Johannes; Cooper, Matthew A.; Blaskovich, Mark A.T.; Hitchens, Jacob R.; Burris-Hiday, Sarah; Tenorio, Kristiana; Mendez, Yanira; Samaritoni, J. Geno; O’Donnell, Martin J.; Scott, William L.; Chemistry and Chemical Biology, School of ScienceNew antibiotics are urgently needed to address increasing rates of multidrug resistant infections. Seventy-six diversely functionalized compounds, comprising five structural scaffolds, were synthesized and tested for their ability to inhibit microbial growth. Twenty-six compounds showed activity in the primary phenotypic screen at the Community for Open Antimicrobial Drug Discovery (CO-ADD). Follow-up testing of active molecules confirmed that two unnatural dipeptides inhibit the growth of Cryptococcus neoformans with a minimum inhibitory concentration (MIC) ≤ 8 μg/mL. Syntheses were carried out by undergraduate students at five schools implementing Distributed Drug Discovery (D3) programs. This report showcases that a collaborative research and educational process is a powerful approach to discover new molecules inhibiting microbial growth. Educational gains for students engaged in this project are highlighted in parallel to the research advances. Aspects of D3 that contribute to its success, including an emphasis on reproducibility of procedures, are discussed to underscore the power of this approach to solve important research problems and to inform other coupled chemical biology research and teaching endeavors.Item Machine-Learning-Assisted Free Energy Simulation of Solution-Phase and Enzyme Reactions(ACS, 2021-09) Pan, Xiaoliang; Yang, Junjie; Van, Richard; Epifanovsky, Evgeny; Ho, Junming; Huang, Jing; Pu, Jingzhi; Mei, Ye; Nam, Kwangho; Shao, Yihan; Chemistry and Chemical Biology, School of ScienceDespite recent advances in the development of machine learning potentials (MLPs) for biomolecular simulations, there has been limited effort on developing stable and accurate MLPs for enzymatic reactions. Here we report a protocol for performing machine-learning-assisted free energy simulation of solution-phase and enzyme reactions at the ab initio quantum-mechanical/molecular-mechanical (ai-QM/MM) level of accuracy. Within our protocol, the MLP is built to reproduce the ai-QM/MM energy and forces on both QM (reactive) and MM (solvent/enzyme) atoms. As an alternative strategy, a delta machine learning potential (ΔMLP) is trained to reproduce the differences between the ai-QM/MM and semiempirical (se) QM/MM energies and forces. To account for the effect of the condensed-phase environment in both MLP and ΔMLP, the DeePMD representation of a molecular system is extended to incorporate the external electrostatic potential and field on each QM atom. Using the Menshutkin and chorismate mutase reactions as examples, we show that the developed MLP and ΔMLP reproduce the ai-QM/MM energy and forces with errors that on average are less than 1.0 kcal/mol and 1.0 kcal mol–1 Å–1, respectively, for representative configurations along the reaction pathway. For both reactions, MLP/ΔMLP-based simulations yielded free energy profiles that differed by less than 1.0 kcal/mol from the reference ai-QM/MM results at only a fraction of the computational cost.Item Interligand communication in a metal mediated LL′CT system – a case study(RSC, 2021) Dille, Sara A.; Colston, Kyle J.; Ratvasky, Stephen C.; Pu, Jingzhi; Basu, Partha; Chemistry and Chemical Biology, School of ScienceA series of oxo-Mo(IV) complexes, [MoO(Dt2−)(Dt0)] (where Dt2− = benzene-1,2-dithiol (bdt), toluene-3,4-dithiol (tdt), quinoxaline-2,3-dithiol (qdt), or 3,6-dichloro-benzene-1,2-dithiol (bdtCl2); Dt0 = N,N′-dimethylpiperazine-2,3-dithione (Me2Dt0) or N,N′-diisopropylpiperazine-2,3-dithione (iPr2Dt0)), possessing a fully oxidized and a fully reduced dithiolene ligand have been synthesized and characterized. The assigned oxidation states of coordinated dithiolene ligands are supported with spectral and crystallographic data. The molecular structure of [MoO(tdt)(iPr2Dt0)] (6) demonstrates a large ligand fold angle of 62.6° along the S⋯S vector of the Dt0 ligand. The electronic structure of this system is probed by density functional theory (DFT) calculations. The HOMO is largely localized on the Dt2− ligand while virtual orbitals are mostly Mo and Dt0 in character. Modeling the electronic spectrum of 6 with time dependent (TD) DFT calculations attributes the intense low energy transition at ∼18 000 cm−1 to a ligand-to-ligand charge transfer (LL′CT). The electron density difference map (EDDM) for the low energy transition depicts the electron rich Dt2− ligand donating charge density to the redox-active orbitals of the electron deficient Dt0 ligand. Electronic communication between dithiolene ligands is facilitated by a Mo-monooxo center and distortion about its primary coordination sphere.Item Reproducible Discovery of Cell-Binding Peptides “Lost” in Bulk Amplification via Emulsion Amplification in Phage Display Panning(Cold Spring Harbor Laboratory Press, 2021) Matochko, Wadim L.; Deiss, Frédérique; Yang, Yang; Derda, Ratmir; Chemistry and Chemical Biology, School of ScienceMany pharmaceutically-relevant cell surface receptors are functional only in the context of intact cells. Phage display, while being a powerful method for the discovery of ligands for purified proteins often fails to identify a diverse set of ligands to receptors on a cell membrane mosaic. To understand this deficiency, we examined growth bias in naïve phage display libraries and observed that it fundamentally changes selection outcomes: The presence of growth-biased (parasite) phage clones in a phage library is detrimental to selection and cell-based panning of such biased libraries is poised to yield ligands from within a small parasite population. Importantly, amplification of phage libraries in water-oil emulsions suppressed the amplification of parasites and steered the selection of biased phage libraries away from parasite population. Attenuation of the growth bias through the use of emulsion amplification reproducibly discovers the ligands for cell-surface receptors that cannot be identified in screen that use conventional ‘bulk’ amplification.Item Kinetic consequences of the endogenous ligand to molybdenum in the DMSO reductase family: a case study with periplasmic nitrate reductase(Springer, 2021-02) Mintmier, Breeanna; McGarry, Jennifer M.; Bain, Daniel J.; Basu, Partha; Chemistry and Chemical Biology, School of ScienceThe molybdopterin enzyme family catalyzes a variety of substrates and plays a critical role in the cycling of carbon, nitrogen, arsenic, and selenium. The dimethyl sulfoxide reductase (DMSOR) subfamily is the most diverse family of molybdopterin enzymes and the members of this family catalyze a myriad of reactions that are important in microbial life processes. Enzymes in the DMSOR family can transform multiple substrates; however, quantitative information about the substrate preference is sparse, and, more importantly, the reasons for the substrate selectivity are not clear. Molybdenum coordination has long been proposed to impact the catalytic activity of the enzyme. Specifically, the molybdenum-coordinating residue may tune substrate preference. As such, molybdopterin enzyme periplasmic nitrate reductase (Nap) is utilized as a vehicle to understand the substrate preference and delineate the kinetic underpinning of the differences imposed by exchanging the molybdenum ligands. To this end, NapA from Campylobacter jejuni has been heterologously overexpressed, and a series of variants, where the molybdenum coordinating cysteine has been replaced with another amino acid, has been produced. The kinetic properties of these variants are discussed and compared with those of the native enzyme, providing quantitative information to understand the function of the molybdenum-coordinating residue.Item Recent Technological Developments for Native Mass Spectrometry(Elsevier, 2022-01) Webb, Ian K.; Chemistry and Chemical Biology, School of ScienceNative mass spectrometry (MS), the analysis of proteins and protein complexes from solutions that stabilize native solution structures, is a rapidly expanding area. There is strong evidence supporting the retention of proteins' native folds in the absence of solvent under the experimental timescales of MS experiments. Therefore, instrumentation has been developed to use gas-phase native-like protein ions to exploit the speed, sensitivity, and selectivity of mass spectrometry approaches to solve emerging problems in structural biology. This article reviews some of the recent advances and applications in gas-phase instrumentation for structural proteomics.Item Vitamin E - phosphatidylethanolamine interactions in mixed membranes with sphingomyelin: Studies by 2H NMR(Elsevier, 2020-09) Cavazos, Andres T.; Kinnun, Jacob J.; Williams, Justin A.; Wassall, Stephen R.; Chemistry and Chemical Biology, School of ScienceAmong the structurally diverse collection of lipids that comprise the membrane lipidome, polyunsaturated phospholipids are particularly vulnerable to oxidation. The role of α-tocopherol (vitamin E) is to protect this influential class of membrane phospholipid from oxidative damage. Whether lipid-lipid interactions play a role in supporting this function is an unanswered question. Here, we compare the molecular organization of polyunsaturated 1-[2H31]palmitoyl-2-docosahexaenoylphosphatidylethanolamine (PDPE-d31) and, as a control, monounsaturated 1-[2H31]palmitoyl-2-oleoylphosphatidylethanolamine (POPE-d31) mixed with sphingomyelin (SM) and α-tocopherol (α-toc) (2:2:1 mol) by solid-state 2H NMR spectroscopy. In both cases the effect of α-toc appears similar. Spectral moments reveal that the main chain melting transition of POPE-d31 and PDPE-d31 is broadened beyond detection. A spectral component attributed to the formation of inverted hexagonal HII phase in coexistence with lamellar Lα phase by POPE-d31 (20 %) and PDPE-d31 (18 %) is resolved following the addition of α-toc. Order parameters in the remaining Lα phase are increased slightly more for POPE-d31 (7%) than PDPE-d31 (4%). Preferential interaction with polyunsaturated phospholipid is not apparent in these results. The propensity for α-toc to form phase structure with negative curvature that is more tightly packed at the membrane surface, nevertheless, may restrict the contact of free radicals with lipid chains on phosphatidylethanolamine molecules that accumulate polyunsaturated fatty acids.Item Blow fly stable isotopes reveal larval diet: A case study in community level anthropogenic effects(Public Library of Science Journals, 2021-04-14) Owings, Charity G.; Gilhooly, William P., III; Picard, Christine J.; Chemistry and Chemical Biology, School of ScienceResponse to human impacts on the environment are typically initiated too late to remediate negative consequences. We present the novel use of stable isotope analysis (SIA) of blow flies to determine human influences on vertebrate communities in a range of human-inhabited environments, from a pristine national park to a dense metropolitan area. The refrain “you are what you eat” applies to the dietary isotope record of all living organisms, and for carrion-breeding blow flies, this translates to the type of carcasses present in an environment. Specifically, we show that carnivore carcasses make up a large proportion of the adult fly’s prior larval diet, which contrasts to what has been reportedly previously for the wild adult fly diet (which consists of mostly herbivore resources). Additionally, we reveal the potential impact of human food on carcasses that were fed on by blow flies, underscoring the human influences on wild animal populations. Our results demonstrate that using SIA in conjunction with other methods (e.g., DNA analysis of flies) can reveal a comprehensive snapshot of the vertebrate community in a terrestrial ecosystem.Item Dimsyl Anion Enables Visible‐Light‐Promoted Charge Transfer in Cross‐Coupling Reactions of Aryl Halides(Wiley, 2022-01) Pan, Lei; Cooke, Maria; Spencer, Amara; Laulhé, Sébastien; Chemistry and Chemical Biology, School of ScienceA methodology is reported for visible-light-promoted synthesis of unsymmetrical chalconides enabled by dimsyl anion in the absence of transition-metals or photoredox catalysts. The cross-coupling reaction between aryl halides and diaryl dichalconides proceeds with electron-rich, electron-poor, and heteroaromatic moieties. Mechanistic investigations using UV−Vis spectroscopy, time-dependent density functional theory (TD-DFT) calculations, and control reactions suggest that dimsyl anion forms an electron-donor-acceptor (EDA) complex capable of absorbing blue light, leading to a charge transfer responsible for generation of aryl radicals from aryl halides. This previously unreported mechanistic pathway may be applied to other light-induced transformations performed in DMSO in the presence of bases and aryl halides.