Neil L Kelleher

Northwestern University, Evanston, Illinois, United States

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Publications (250)1828.5 Total impact

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    ABSTRACT: Histones, and their modifications, are critical components of cellular programming and epigenetic inheritance. Recently, cancer genome sequencing has uncovered driver mutations in chromatin modifying enzymes spurring high interest how such mutations change histone modification patterns. Here, we applied Top-Down mass spectrometry for the characterization of combinatorial modifications (i.e., methylation and acetylation) on full length histone H3 from human cell lines derived from multiple myeloma patients with overexpression of the histone methyltransferase MMSET as the result of a t(4;14) chromosomal translocation. Using the latest in Orbitrap-based technology for clean isolation of isobaric proteoforms containing up to 10 methylations and/or up to 2 acetylations, we provide extensive characterization of histone H3.1 and H3.3 proteoforms. Differential analysis of modifications by electron-based dissociation recapitulated antagonistic crosstalk between K27 and K36 methylation in H3.1, validating that full-length histone H3 (15 kDa) can be analyzed with site-specific assignments for multiple modifications. It also revealed K36 methylation in H3.3 was affected less by the overexpression of MMSET due to its higher methylation levels in control cells. The co-occurrence of acetylation with a minimum of three methyl groups in H3K9 and H3K27 suggested a hierarchy in the addition of certain modifications. Comparative analysis showed that high levels of MMSET in the myeloma-like cells drove the formation of hypermethyled proteoforms containing H3K36me2 co-existent with the repressive marks H3K9me2/3 and H3K27me2/3. Unique histone proteoforms with such "trivalent hypermethylation" (K9me2/3-K27me2/3-K36me2) were not discovered when H3.1 peptides were analyzed by Bottom-Up. Such disease-correlated proteoforms could link tightly to aberrant transcription programs driving cellular proliferation, and their precise description demonstrates that Top-Down mass spectrometry can now decode crosstalk involving up to three modified sites. Copyright © 2015, The American Society for Biochemistry and Molecular Biology.
    Molecular &amp Cellular Proteomics 08/2015; DOI:10.1074/mcp.M115.053819 · 7.25 Impact Factor
  • Owen S Skinner · Neil L Kelleher
    Nature Biotechnology 07/2015; 33(7):717-8. DOI:10.1038/nbt.3287 · 39.08 Impact Factor
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    ABSTRACT: When γ-aminobutyric acid (GABA), the major inhibitory neurotransmitter in the mammalian central nervous system, falls below a threshold level, seizures occur. One approach to raise GABA concentrations is to inhibit GABA aminotransferase (GABA-AT), a pyridoxal 5'-phosphate-dependent enzyme that degrades GABA. We have previously developed (1S,3S)-3-amino-4-difluoromethylene-1-cyclopentanoic acid (CPP-115), which is 186 times more efficient in inactivating GABA-AT than vigabatrin, the only FDA-approved inactivator of GABA-AT. We also developed (E)- and (Z)-(1S,3S)-3-amino-4-fluoromethylenyl-1-cyclopentanoic acid (1 and 2, respectively), monofluorinated analogs of CPP-115, which are comparable to vigabatrin in inactivat-ing GABA-AT. Here we report the mechanism of inactivation of GABA-AT by 1 and 2. Both produce a metabolite that induces disruption of the Glu270-Arg445 salt bridge to accommodate interaction between the metabolite formyl group and Arg445. This is the second time that Arg445 has interacted with a ligand and is involved in GABA-AT inactivation, thereby confirming the im-portance of Arg445 in future inactivator design.
    ACS Chemical Biology 06/2015; [Epub ahead of print]. DOI:10.1021/acschembio.5b00212 · 5.36 Impact Factor
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    ABSTRACT: Enabling the implementation of top down proteomic techniques within clinical workflows requires a dramatic increase in sensitivity. It has been previously demonstrated that electrospray ionization (ESI) becomes more efficient with decreasing volumetric flow rates at the emitter. Therefore, narrow inner diameter (I.D.) columns used in front-end chromatographic separations yield increased sensitivity. However, the smaller cross-sectional area of a narrow I.D. column places a larger fraction of the eluent in fluid communication with the electrode within the high voltage union that facilitates electrospray ionization (ESI), leading to increased oxidation of solution-phase proteins. Oxidation of proteins alters their chemical state of the protein, complicates data analysis, and reduces the depth of proteome coverage attained in a typical top-down proteomics experiment. Excessive protein oxidation results in poor deconvolution and exact mass calculations from MS1 spectra, interferes with peak isolation for MS/MS fragmentation, and effectively reduces sensitivity by splitting ion current. All of these factors deteriorate top down mass spectral data quality, an effect that becomes more pronounced as column diameter decreases. Artificial protein oxidation can also mislead investigations of in vivo protein oxidation. All of these effects are accentuated in comparison to bottom up proteomics due to the increased probability of having oxidizable residues within a particular species with increasing mass. Herein, we describe a configuration (which we term “Low Protein Oxidation (LPOx)”) for proteomics experiments created by re-arranging liquid chromatography (LC) plumbing and present its application to artificial protein oxidation and show a marked improvement in detection sensitivity. Using a standard mixture of five intact proteins, we demonstrate that the LPOx configuration reduces protein oxidation up to 90% using 50 μm I.D. columns when compared to a conventional LC plumbing configuration with 50 μm I.D. column. As a proof-of-concept study, at least 11 distinct proteoforms of serum Apolipoprotein A1 were detected with the LPOx configuration. This innovative LC configuration can be applied to the top down identification and characterization of proteoforms obscured by abundant artificial protein oxidation at low flowrates, all while using reduced amounts of valuable protein samples.
    06/2015; 7. DOI:10.1016/j.euprot.2015.05.005
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    ABSTRACT: Measuring post-translational modifications on transcription factors by targeted mass spectrometry is hampered by low protein abundance and inefficient isolation. Here, we utilized HaloTag technology to overcome these limitations and evaluate various top down mass spectrometry approaches for measuring NF-κB p65 proteoforms isolated from human cells. We show isotopic resolution of N-terminally acetylated p65 and determined it is the most abundant proteoform expressed following transfection in 293 T cells. We also show MS1 evidence for monophosphorylation of p65 under similar culture conditions and describe a high propensity for p65 proteoforms to fragment internally during beam-style MS2 fragmentation; up to 71% of the fragment ions could be matched as internals in some fragmentation spectra. Finally, we used native spray mass spectrometry to measure proteins copurifying with p65 and present evidence for the native detection of p65, 71 kDa heat shock protein, and p65 homodimer. Collectively, our work demonstrates the efficient isolation and top down mass spectrometry analysis of p65 from human cells, and we discuss the perturbations of overexpressing tagged proteins to study their biochemistry.
    Journal of proteomics 05/2015; DOI:10.1016/j.jprot.2015.04.025 · 3.93 Impact Factor
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    ABSTRACT: With thousands of fungal genomes being sequenced, each genome containing up to 70 secondary metabolite (SM) clusters 30-80 kb in size, breakthrough techniques are needed to characterize this SM wealth. Here we describe a novel system-level methodology for unbiased cloning of intact large SM clusters from a single fungal genome for one-step transformation and expression in a model host. All 56 intact SM clusters from Aspergillus terreus were individually captured in self-replicating fungal artificial chromosomes (FACs) containing both the E. coli F replicon and an Aspergillus autonomously replicating sequence (AMA1). Candidate FACs were successfully shuttled between E. coli and the heterologous expression host A. nidulans. As proof-of-concept, an A. nidulans FAC strain was characterized in a novel liquid chromatography-high resolution mass spectrometry (LC-HRMS) and data analysis pipeline, leading to the discovery of the A. terreus astechrome biosynthetic machinery. The method we present can be used to capture the entire set of intact SM gene clusters and/or pathways from fungal species for heterologous expression in A. nidulans and natural product discovery.
    BMC Genomics 04/2015; 16(1):343. DOI:10.1186/s12864-015-1561-x · 4.04 Impact Factor
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    ABSTRACT: Nitric oxide synthase (NOS) catalyzes the conversion of L-arginine to L-citrulline and the second messenger nitric oxide. Three mechanistic pathways are proposed for the inactivation of neuronal NOS (nNOS) by (S)-2-amino-5-(2-(methylthio)acetimidamido)pentanoic acid (1): sulfide oxidation, oxidative dethiolation, and oxidative demethylation. Four possible intermediates were synthesized. All compounds were assayed with nNOS, their IC50, KI, and kinact values obtained, and their crystal structures determined. The identification and characterization of products formed during inactivation provide evidence for the details of the inactivation mechanism. On the basis of these studies, the most probable mechanism for the inactivation of nNOS involves oxidative demethylation with the resulting thiol coordinating to the cofactor heme iron. Although nNOS is a heme-containing enzyme, this is the first example of a NOS that catalyzes an S-demethylation reaction; the novel mechanism of inactivation described here could be applied to the design of inactivators of other heme-dependent enzymes.
    Journal of the American Chemical Society 04/2015; 137(18). DOI:10.1021/jacs.5b01202 · 11.44 Impact Factor
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    ABSTRACT: A fractionation method called Gel Eluted Liquid Fraction Entrapment Electrophoresis (GELFrEE) has been used to dramatically increase the number of proteins identified in top-down proteomic workflows. However, the technique involves the use of sodium dodecyl sulfate (SDS), a surfactant that interferes with electrospray ionization. Therefore, an efficient removal of SDS is absolutely required prior to mass analysis. Traditionally, methanol/chloroform precipitation and spin columns have been used but they lack reproducibility and are difficult to automate. Therefore, we developed an in-line matrix removal platform to enable the direct analysis of samples containing SDS and salts. Only small molecules like SDS permeate a porous membrane and are removed in a manner similar to cross flow filtration. With this device, near complete removal of SDS is accomplished within 5 minutes and proteins are subsequently mobilized into a mass spectrometer. The new platform was optimized for analysis of GELFrEE fractions enriched for histones extracted from human HeLa cells. All four core histones and their proteoforms were detected in a single spectrum by high-resolution mass spectrometry. The new method vs. protein precipitation/resuspension showed 2- to 10-fold improved signal intensities, offering a clear path forward to improve proteome coverage and the efficiency of top-down proteomics.
    Journal of Proteome Research 04/2015; 14(5). DOI:10.1021/pr501331q · 5.00 Impact Factor
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    ABSTRACT: The microbial world offers a rich source of bioactive compounds for those able to sift through it. Technologies capable of quantitatively detecting natural products while simultaneously identifying known compounds would expedite the search for new pharmaceutical leads. Prior efforts have targeted histone deacetylases in fungi to globally activate the production of new secondary metabolites, yet no study has directly assessed its effects with minimal bias at the metabolomic level. Using untargeted metabolomics, we monitored changes in >1000 small molecules secreted from the model fungus, Aspergillus nidulans, following genetic or chemical reductions in histone deacetylase activity (HDACi). Through quantitative, differential analyses, we found nearly equal numbers of compounds were up- and down-regulated by >100 fold. We detected products from both known and unknown biosynthetic pathways and discovered that A. nidulans is capable of producing fellutamides, proteasome inhibitors whose expression was induced by ~100 fold or greater upon HDACi. This work adds momentum to an 'omics'-driven resurgence in natural products research, where direct detection replaces bioactivity as the primary screen for new pharmacophores.
    ACS Chemical Biology 03/2015; 10(6). DOI:10.1021/acschembio.5b00025 · 5.36 Impact Factor
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    ABSTRACT: Low levels of γ-aminobutyric acid (GABA), one of two major neurotransmitters that regulate brain neuronal activity, are associated with many neurological disorders, such as epilepsy, Parkinson's disease, Alzheimer's disease, Huntington's chorea, and cocaine addiction. One of the main methods to raise the GABA level in human brain is to use small molecules that cross the blood-brain barrier and inhibit the activity of γ-aminobutyric acid aminotransferase (GABA-AT), the enzyme that degrades GABA. We have designed a series of conformationally-restricted, tetrahydrothiophene-based GABA analogs with a properly-positioned leaving group that could facilitate a ring-opening mechanism, leading to inactivation of GABA-AT. One compound in the series is eight times more efficient an inactivator of GABA-AT than vigabatrin, the only FDA-approved inactivator of GABA-AT. Our mechanistic studies show that the compound inactivates GABA-AT by a new mechanism. The metabolite resulting from inactivation does not covalently bind to amino acid residues of GABA-AT but stays in the active site via H-bond interactions with Arg-192, a π-π interaction with Phe-189, and a weak nonbonded S···O=C interaction with Glu-270, thereby inactivating the enzyme.
    Journal of the American Chemical Society 03/2015; 137(13). DOI:10.1021/jacs.5b01155 · 11.44 Impact Factor
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    ABSTRACT: Site-specific incorporation of non-standard amino acids (NSAAs) into proteins opens the way to novel biological insights and applications in biotechnology. Here, we describe the development of a high yielding cell-free protein synthesis (CFPS) platform for NSAA incorporation from crude extracts of genomically recoded Escherichia coli lacking release factor 1. We used genome engineering to construct synthetic organisms that, upon cell lysis, lead to improved extract performance. We targeted five potential negative effectors to be disabled: the nuclease genes rna, rnb, csdA, mazF, and endA. Using our most productive extract from strain MCJ.559 (csdA(-) endA(-) ), we synthesized 550±40 μg mL(-1) of modified superfolder green fluorescent protein containing p-acetyl-L-phenylalanine. This yield was increased to ∼1300 μg mL(-1) when using a semicontinuous method. Our work has implications for using whole genome editing for CFPS strain development, expanding the chemistry of biological systems, and cell-free synthetic biology. © 2015 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.
    ChemBioChem 03/2015; 16(5). DOI:10.1002/cbic.201402708 · 3.06 Impact Factor
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    ABSTRACT: Gaseous fragmentation of intact proteins is multifaceted and can be unpredictable by current theories in the field. Contributing to the complexity is the multitude of precursor ion states and fragmentation channels. Terminal fragment ions can be re-fragmented, yielding product ions containing neither terminus, termed internal fragment ions. In an effort to better understand and capitalize upon this fragmentation process, we collisionally dissociated the high (13+), middle (10+), and low (7+) charge states of electrosprayed ubiquitin ions. Both terminal and internal fragmentation processes were quantified through step-wise increases of voltage potential in the collision cell. An isotope fitting algorithm matched observed product ions to theoretical terminal and internal fragment ions. At optimal energies for internal fragmentation of the 10+, nearly 200 internal fragments were observed; on average each of the 76 residues in ubiquitin was covered by 24.1 internal fragments. A pertinent finding was that formation of internal ions occurs at similar energy thresholds as terminal b- and y-ion types in beam-type activation. This large amount of internal fragmentation is frequently overlooked during top-down mass spectrometry. As such, we present several new approaches to visualize internal fragments through modified graphical fragment maps. With the presented advances of internal fragment ion accounting and visualization, the total percentage of matched fragment ions increased from approximately 40% to over 75% in a typical beam-type MS/MS spectrum. These sequence coverage improvements offer greater characterization potential for whole proteins with no needed experimental changes and could be of large benefit for future high-throughput intact protein analysis.
    Journal of the American Society for Mass Spectrometry 02/2015; 26(5). DOI:10.1007/s13361-015-1078-1 · 3.19 Impact Factor
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    ABSTRACT: The cadre of protein complexes in cells performs an array of functions necessary for life. Their varied structures are foundational to their ability to perform biological functions, lending great import to the elucidation of complex composition and dynamics. Native separation techniques that are operative on low sample amounts and provide high resolution are necessary to gain valuable data on endogenous complexes. Here, we detail and optimize the use of tube gel separations to produce samples proven compatible with native, multistage mass spectrometry (nMS/MS). We find that a continuous system (i.e., no stacking gel) with a gradient in its extent of crosslinking and use of the clear native buffer system performs well for both fractionation and native mass spectrometry of heart extracts and a fungal secretome. This integrated advance in separations and nMS/MS offers the prospect of untargeted proteomics at the next hierarchical level of protein organization in biology.
    Analytical Chemistry 02/2015; 87(5). DOI:10.1021/ac504678d · 5.83 Impact Factor
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    ABSTRACT: γ-Aminobutyric acid aminotransferase (GABA-AT) is a pyridoxal 5'-phosphate (PLP)-dependent enzyme that degrades GABA, the principal inhibitory neurotransmitter in mammalian cells. When the concentration of GABA falls below a threshold level, convulsions can occur. Inhibition of GABA-AT raises GABA levels in the brain, which can terminate seizures as well as have potential therapeutic applications in treating other neurological disorders, including drug addiction. Among the analogues that we previously developed, (1S,3S)-3-amino-4,4-difluoromethylenyl-1-cyclopentanoic acid (CPP-115) showed 187 times greater potency than vigabatrin, a known inactivator of GABA-AT and approved drug (SabrilTM) for the treatment of infantile spasms and refractory adult epilepsy. Recently, CPP-115 was shown to have no adverse effects in a Phase I clinical trial. Here we report a novel inactivation mechanism for CPP-115, a mechanism-based inactivator that undergoes GABA-AT-catalyzed hydrolysis of the difluoromethylenyl group to a carboxylic acid with concomitant loss of two fluoride ions and coenzyme conversion to pyridoxamine 5'-phosphate (PMP). The partition ratio for CPP-115 with GABA-AT is about 2000, releasing cyclopentanone-2,4-dicarboxylate (22) and two other precursors of this compound (20 and 21). Time-dependent inactivation occurs by a conformational change induced by the formation of the aldimine of 4-aminocyclopentane-1,3-dicarboxylic acid and PMP (20), which disrupts an electrostatic interaction between Glu270 and Arg445 to form an electrostatic interaction between Arg445 and the newly-formed carboxylate produced by hydrolysis of the difluoromethylenyl group in CPP-115, resulting in a noncovalent, tightly bound complex. This represents a novel mechanism for inactivation of GABA-AT and a new approach for the design of mechanism-based inactivators in general.
    Journal of the American Chemical Society 01/2015; 137(7). DOI:10.1021/ja512299n · 11.44 Impact Factor
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    ABSTRACT: This paper describes how pH can be used to control covalent attachment of oligonucleotides with secondary structure on gold nanoparticles (AuNPs). The highest loading of thiolated nucleic acids occurred at low pH (pH = 1.7) due to reduced repulsion between the negatively charged oligonucleotides and the AuNP surface. The packing of oligonucleotides at low pH decreased (single-stranded > duplex > quadruplex) as the spatial footprint of the secondary structure increased. As the pH increased, a decrease in the number of DNA strands grafted to the AuNPs was observed. Notably, the loading density depended on the flexibility and spatial organization of the secondary structures at all pH conditions. At the lowest pH tested, circular dichroism analysis revealed that G-quadruplex aptamers underwent a structural change (from parallel to anti parallel or vice versa), although the biological activity of the aptamer-loaded AuNPs was still maintained. We anticipate that pH-tuning can result in quantitative loading of oligonucleotides on various types of AuNPs with different shapes and surface capping layers.
    Bioconjugate Chemistry 01/2015; 26(2). DOI:10.1021/bc500562s · 4.82 Impact Factor
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    ABSTRACT: Filamentous fungi and bacteria form mixed-species biofilms in nature and diverse clinical contexts. They secrete a wealth of redox-active small molecule secondary metabolites, which are traditionally viewed as toxins that inhibit growth of competing microbes. Here, we report that these "toxins" can act as interspecies signals, affecting filamentous fungal development via oxidative stress regulation. Specifically, in coculture biofilms, Pseudomonas aeruginosa phenazine-derived metabolites differentially modulated Aspergillus fumigatus development, shifting from weak vegetative growth to induced asexual sporulation (conidiation) along a decreasing phenazine gradient. The A. fumigatus morphological shift correlated with the production of phenazine radicals and concomitant reactive oxygen species (ROS) production generated by phenazine redox cycling. Phenazine conidiation signaling was conserved in the genetic model A. nidulans and mediated by NapA, a homolog of AP-1-like bZIP transcription factor, which is essential for the response to oxidative stress in humans, yeast, and filamentous fungi. Expression profiling showed phenazine treatment induced a NapA-dependent response of the global oxidative stress metabolome, including the thioredoxin, glutathione, and NADPH-oxidase systems. Conidiation induction in A. nidulans by another microbial redox-active secondary metabolite, gliotoxin, also required NapA. This work highlights that microbial redox metabolites are key signals for sporulation in filamentous fungi, which are communicated through an evolutionarily conserved eukaryotic stress response pathway. It provides a foundation for interspecies signaling in environmental and clinical biofilms involving bacteria and filamentous fungi. Copyright © 2015 Elsevier Ltd. All rights reserved.
    Current Biology 12/2014; 25(1). DOI:10.1016/j.cub.2014.11.018 · 9.92 Impact Factor
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    ABSTRACT: Many top-down proteomics experiments focus on identifying and localizing post-translational modifications and other potential sources of “mass shift” on a known protein sequence. A simple application to match ion masses and facilitate the iterative hypothesis testing of PTM presence and location would assist with the data analysis in these experiments. ProSight Lite is a free software tool for matching a single candidate sequence against a set of mass spectrometric observations. Fixed or variable modifications, including both post-translational modifications and a select number of glycosylations, can be applied to the amino acid sequence. The application reports multiple scores and a matching fragment list. Fragmentation maps can be exported for publication in either PNG or SVG format. ProSight Lite can be freely downloaded from http://prosightlite.northwestern.edu, installs and updates from the web, and requires Windows 7 or higher.This article is protected by copyright. All rights reserved
    Proteomics 12/2014; 15(7). DOI:10.1002/pmic.201400313 · 3.97 Impact Factor
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    ABSTRACT: It has long been understood that it is proteins, expressed and post-translationally modified, that are the primary regulators of both the fate and the function of cells. The ability to measure differences in the expression of the constellation of unique protein forms (proteoforms) with complete molecular specificity has the potential to sharply improve the return on investment for mass spectrometry-based proteomics in translational research and clinical diagnostics.
    Expert Review of Proteomics 10/2014; 11(6):1-3. DOI:10.1586/14789450.2014.976559 · 3.54 Impact Factor
  • AIDS Research and Human Retroviruses 10/2014; 30 Suppl 1(S1):A154. DOI:10.1089/aid.2014.5315.abstract · 2.46 Impact Factor
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    ABSTRACT: We employ stable isotope labelling and quantitative mass spectrometry to track histone methylation stability. We show that H3 trimethyl K9 and K27 are slow to be established on new histones and slow to disappear from old histones, with half-lives of multiple cell divisions. By contrast the transcription-associated marks K4me3 and K36me3 turn over far more rapidly, with half-lives of 6.8 h and 57 h, respectively. Inhibition of demethylases increases K9 and K36 methylation, with K9 showing the largest and most robust increase. We interpret different turnover rates in light of genome-wide localization data and transcription-dependent nucleosome rearrangements proximal to the transcription start site.This article is protected by copyright. All rights reserved
    Proteomics 10/2014; 14(19). DOI:10.1002/pmic.201400060 · 3.97 Impact Factor

Publication Stats

11k Citations
1,828.50 Total Impact Points

Institutions

  • 2010–2015
    • Northwestern University
      • • Chemistry of Life Processes Institute
      • • Department of Chemistry
      Evanston, Illinois, United States
  • 2013
    • Ann & Robert H. Lurie Children's Hospital of Chicago
      Chicago, Illinois, United States
  • 2000–2013
    • University of Illinois, Urbana-Champaign
      • • Department of Chemistry
      • • Institute for Genomic Biology
      • • Department of Computer Science
      Urbana, Illinois, United States
  • 2008
    • McMaster University
      • Department of Biochemistry and Biomedical Sciences
      Hamilton, Ontario, Canada
  • 2007–2008
    • Urbana University
      Urbana, Illinois, United States
  • 1999–2007
    • Harvard University
      Cambridge, Massachusetts, United States
  • 1998–2006
    • Harvard Medical School
      • Department of Biological Chemistry and Molecular Pharmacology
      Boston, Massachusetts, United States
  • 1996–2000
    • Cornell University
      • Department of Chemistry and Chemical Biology
      Итак, New York, United States
  • 1994
    • Baker University
      • Chemistry
      New York, New York, United States