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Report from the Seventh Annual ‘Frontiers at the Chemistry Biology Interface Symposium’ Sarah L. J. Michel* Department of Pharmaceutical Sciences, University of Maryland School of Pharmacy, Baltimore, Maryland 21201, United States he Seventh Annual ‘Frontiers at the Chemistry Biology Interface’ symposium was held on Saturday, May 10, 2014. This symposium series was originally conceived by Professor Steve Rokita (then at University of Maryland College Park and now at Johns Hopkins University), after attending a symposium to celebrate Professor Philip Cole’s arrival as Department Chair of Pharmacology at Johns Hopkins University School of Medicine. The first meeting was organized by Professors Rokita (UMCP), Craig Townsend (Johns Hopkins University), John Koh (University of Delaware), and James Fishbein (University of Maryland Baltimore County) in 2008. This yearly symposium brings together researchers from the Mid-Atlantic for a day of science at the Chemistry and Biology interface. Over the years, additional partners have joined as organizers, including the University of Pennsylvania, the Wistar Institute, and this year, the University of Maryland Baltimore School of Pharmacy. More than 200 researchers from academia, industry, and government gathered at the downtown Baltimore Campus of the University of Maryland School of Pharmacy for this year’s symposium, which was hosted by the School’s Department of Pharmaceutical Sciences (PSC). The meeting included a series of lectures by ‘rising stars’ from Universities in the Mid-Atlantic, two poster sessions, a keynote lecture by Professor James Berger from the Johns Hopkins University School of Medicine, and a career panel for students that included colleagues from the private sector, government, and academic laboratories. Professor Sarah Michel (symposium organizer) and Professor Andrew Coop (PSC department chair) opened the meeting with welcoming remarks. The first session, moderated by Professor Steve Fletcher from PSC, began with a presentation by Professor Paul Paukstelis from the Department of Chemistry and Biochemistry, University of Maryland College Park. Dr. Paukstelis described his group’s efforts to utilize nonWatson−Crick base-pairing motifs to design three-dimensional DNA crystals. Obtaining this crystal morphology is a longstanding goal of the DNA nanotechnology field for applications that include host−guest crystallization of proteins and for the assembly of molecular electronics. Dr. Paukstelis presented work by his laboratory in which a parallel-stranded 5′-GGA was conjugated to canonical Watson−Crick pairs to form an expanded crystal lattice with a large (9 nm in diameter) solvent channel that runs through the length of the crystals. Dr. Paukstelis and co-workers then demonstrated that they could adsorb RNaseA to the lattice and retain enzymatic activity. The potential applications of this new biomaterial include enzyme replacement therapy and biodegradable catalysts. Dr. Paukstelis also described his laboratory’s success in creating pHresponsive DNA crystals via a 5′-CGAA parallel base-pairing
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motif as a first step toward the development of environmentally responsive biomaterials.1 Professor Dominque Frueh from the Department of Biophysics and Biophysical Chemistry at the Johns Hopkins University School of Medicine presented the second lecture. In his talk, Dr. Frueh described a series of NMR methods that his laboratory has employed to characterize large multi-domain nonribosomal peptide synthetases (NRPSs). His laboratory has demonstrated that aryl carrier proteins (ArCP) interact with chemical substrates tethered to the end of the 20 Å long phosphopantetheinyl arm present in holo-ArCP. By measuring NMR relaxation rates, Dr. Frueh and his group have determined that that ArCPs are subject to considerable dynamics. Dr. Frueh also described a software package that his laboratory has developed that permits accurate analysis of NMR relaxation data obtained within a sixth of the acquisition time needed with conventional techniques. In addition, he described spectral manipulations that facilitate NMR resonance Published: September 19, 2014 1915
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Scientist II, BD Biosciences; Dr. Jacqueline Heilman, Scientific Consultant, Exponent; Dr. Patrick McTamney, Scientist I at MedImmune LLC; Dr. Veronika Szalai, Project Leader, Energy Research Group, NIST; and Dr. Douglas Cerasoil, Research Microbiologist, United States Army Medical Research Institute of Chemical Defense. After describing how they reached their present positions, the panel took questions from the audience, and a lively discussion regarding scientific careers followed. The afternoon session, moderated by Professor Fengtian Xue from PSC, opened with a talk by PSC faculty member Professor Maureen Kane about her laboratory’s efforts to develop metabolomics to characterize tissue dysfunction and repair. Working as part of the Medical Countermeasures Against Radiological Threat consortium at the University of Maryland Baltimore, Dr. Kane’s laboratory is utilizing mass spectrometrybased metabolomic approaches to characterize biomarkers that can inform on the extent of radiation-induced tissue injury and the efficacy of therapeutic countermeasures to repair radiation damage. Dr. Kane’s presentation included examples of how her laboratory is using targeted metabolomics, LC−MS profiling, and mass spectrometry imaging for biomarker discovery and quantification.5 Prof. Young-Sam Lee from the Department of Biology, The Johns Hopkins University followed Dr. Kane with a talk focused on his laboratory’s recent findings that ligand binding can induce protein kinase activity from a pyruvate kinase isoform. He reported that the binding of SAICAR, a nucleotide biosynthesis intermediate to pyruvate kinase M2 induces protein kinase activity and promotes cancer cell proliferation.6 This finding is an important first step in understanding how cellular metabolites regulate cancer cell growth and metabolism. Professor Marcin Ptaszek from the Department of Chemistry and Biochemistry, University of Maryland Baltimore County concluded the afternoon session with a talk describing his laboratory’s efforts to prepare tunable macromolecules for fluorescence-guided surgery. The Ptaszek lab is developing a family of tetrapyrollic macrocycles called bacteriochlorins for use in tumor detection. Dr. Ptaszek presented his laboratory’s development of a bacteriochlorin conjugated to galactosylated human serum albumin (gHSA); this conjugate allows for direct visualization of ovarian cancers.7 Buoyed by the success of this conjugate, the Ptaszek laboratory has designed and synthesized a large family energy transfer dyads composed of chlorinbacteriochlorin conjugates. These dyads can be tuned to different emission profiles based on modifying the macrocycle functionality and have great potential in fluorescence guided tumor surgery. The second poster session followed with presentations on topics ranging from the design and synthesis of new drugs to treat tamoxifen-resistant cancers to biomarker discovery using MALDI-MS imaging. Following the poster session, Professor James Berger from the Department of Biophysics and Biophysical Chemistry, the Johns Hopkins University School presented the keynote lecture. Professor Berger presented structural and biochemical data focused on understanding how ring-shaped hexameric helicases and translocases convert the chemical energy of ATP into directed motion.8 Structures of the E. coli Rho transcription termination factor bound to RNA and nonhydrolyzable nucleotide analogues indicate that this RNA/DNA helicase uses a rotary, asymmetrically organized arrangement of ATPase states to control the translocation of the motor along a nucleic acid substrate, with a likely step size of one ATP consumed per
assignment in larger proteins, using the 37 kDa NRPS domain as an example.2 The first of two poster sessions followed Dr. Frueh’s talk. Posters with topics ranging from novel semisynthetic approaches to prepare proteins for the development of inhibitors of ubiquitination were presented. The second set of morning lectures were moderated by PSC faculty member Professor Jana Shen. Professor April Kloxin from the Department of Chemical and Biochemical Engineering at the University of Delaware opened the session with a talk describing her laboratory’s successes in designing dynamic biomaterials for the cell. Dr. Kloxin described the design and preparation of responsive biomimetic materials that can be utilized to control the cellular microenvironment in space and time to investigate key regulators of tissue regeneration or disease, including dormancy and reactivation of cancer cells in late cancer recurrence. Using photoinitiated thiol−ene “click” chemistry, her laboratory has prepared hydrogels from vinylfunctionalized peptides and thiol-functionalized poly(ethylene glycol) under cytocompatible conditions for cell encapsulation and culture, including human mesenchymal stem cells and breast cancer cells (MCF7s). These synthetic matrices mimic the elasticity or “stiffness” of various soft tissues (Young’s moduli (E) ∼1 to 10 kPa) and enable the presentation of biochemical cues, such as integrin-binding peptides derived from extracellular matrix (ECM) proteins (RGDS). A unique aspect of these materials is that they are based upon simple molecular building blocks, which are commercially available or easily synthesized, making these well-defined matrices widely accessible for cell culture and delivery.3 Following Dr. Kloxin, Professor Rahul Kohli from the Departments of Medicine and of Biochemistry and Biophysics at the University of Pennsylvania described a novel approach his laboratory is taking to combat antibiotic-resistant bacteria. Current approaches to the shrinking antibiotic arsenal involve chemically modifying known antibiotic scaffolds to overcome resistance mechanisms or identifying new essential genes as targets for novel therapies. The Kohli lab is pursuing an alternative strategy, focused on understanding and targeting the mechanisms by which bacteria adapt to antibiotics and acquire resistance. This anti-evolutionary approach, aimed at potentiating current antibiotics, is focused on the stress response or SOS pathway in bacteria, a DNA damage response pathway that can be highly error-prone and thereby promotes acquired drug resistance. The pathway is under the control of a bifunctional repressor protease, LexA, which has to undergo autoproteolysis (self-cleavage) to initiate the SOS response. Dr. Kohli described his laborabory’s recently published work that elucidates the substrate specificity of LexA and is now being used to inform rational efforts to target this self-cleavage reaction.4 The laboratory has used this study to create bacterial strains of E. coli that contain LexA enzymes that are hypo- or hypercleavable. Dr. Kohli described his laboratory’s newest evidence suggesting that the fitness of the bacteria and their likelihood of acquiring drug resistance in these strains could be modulated by altering the LexA cleavage rate. These stimulating results suggest that efforts to target this self-cleavage reaction with small molecules could be a novel way to approach the problem of acquired antibiotic resistance. The meeting then broke for lunch, and students and postdoctoral fellows were invited to join a lunchtime career panel. The panel included Dr. Gregory Gatto, Senior Scientific Investigator, GlaxoSmithKline; Dr. Nujeevan Dosanjh, R&D 1916
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acceptors with tunable emission wavelength. J. Org. Chem. 78, 10678− 10691. (8) O’Shea, V. L., and Berger, J. M. (2014) Loading strategies of ringshaped nucleic acid translocases and helicases. Curr. Opin. Struct. Biol. 25, 16−24.
base step. Comparison of Rho, a RecA-family ATPase, with the papilloma virus E1 protein, an AAA+ family ATPase, suggests that the two hexameric helicases move in opposite directions along substrates by switching the direction in which an ATPase wave propagates around the ring. Dr. Berger also presented data showing how the Rho ring interconverts between an openring loading state and a closed-ring translocation form and how RNA, ATP, and small molecule agents can control these conformational transitions. The meeting concluded with a poster award, sponsored by ACS Chemical Biology. Mr. Serge Yvon Ongagna-Yhomb from the University of Delaware was awarded the prize for his poster entitled “Investigating the role of the putative Betaine/ Carnitine/Choline Transporter (BCCT) in the halophile Vibrio parahaemolyticus”. Planning has already begun for the Eighth Frontiers at the Chemistry/Biology Interface Symposium. This meeting will be hosted by the Chemistry and Biochemistry Department at the University of Maryland Baltimore County, with Professor James Fishbein as organizer. As per tradition, registration will be free, and all are encouraged to attend and present their work.
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AUTHOR INFORMATION
Corresponding Author
*E-mail:
[email protected].
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ACKNOWLEDGMENTS The following organizations provided support for the symposium. University of Maryland School of Pharmacy Department of Pharmaceutical Sciences, Johns Hopkins University CBI Program, Johns Hopkins University Department of Chemistry, Johns Hopkins University School of Medicine, University of Delaware Department of Chemistry and Biochemistry, University of Pennsylvania Department of Chemistry, ACS Chemical Biology, Fisher Scientific, ISS, Waters, and the Wistar Institute. The following colleagues were instrumental in organizing the meeting: Professors Jana Shen (UMB School of Pharmacy), Steve Rokita (JHU), Caren Meyers (JHU), Millicent Sullivan (U. Delaware) E. James Peterson and Ronen Marmorstein (U. Penn), Herman Sintim (UMCP), and James Fishbein (UMBC). S.L.J.M. acknowledges the support of NSF (CHE-1306208).
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REFERENCES
(1) Geng, C., and Paukstelis, P. J. (2014) DNA crystals as vehicles for biocatalysis. J. Am. Chem. Soc. 136, 7817−20. (2) Harden, B. J., and Frueh, D. P. (2014) SARA: a software environment for the analysis of relaxation data acquired with accordion spectroscopy. J. Biomol. NMR 58, 83−99. (3) Smithmyer, M. E., Sawicki, L. A., and Kloxin, A. M. (2014) Hydrogel scaffolds as in vitro models to study fibroblast activation in wound healing and disease. Biomater. Sci. 2, 634−650. (4) Mo, C. Y., Birdwell, L. D., and Kohli, R. M. (2014) Specificity determinants for autoproteolysis of LexA, a key regulator of bacterial SOS mutagenesis. Biochemistry 20, 3158−68. (5) Jones, J. W., Scott, A. J., Tudor, G., Jackson, I. L., Vujaskovic, Z., Booth, C., MacVittie, T. J., Ernst, R. K., and Kane, M. A. (2014) Identification and quantitation of biomarkers for radiation-induced injury via mass spectrometry. Health Phys. 106, 106−19. (6) Keller, K. E., Doctor, Z. M., Dwyer, Z. W., and Lee, Y. S. (2014) SAICAR induces protein kinase activity of PKM2 that is necessary for sustained proliferative signaling of cancer cells. Mol. Cell 53, 700−9. (7) Yu, Z., and Ptaszek, M. (2013) Near-IR emissive chlorinbacteriochlorin energy-transfer dyads with a common donor and 1917
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