Biophysical Chemistry

Megan L. Matthews

Photo: 
First Name: 
Megan L.
Last Name: 
Matthews
Official Title: 
Assistant Professor of Chemistry
Contact Information
Office Location: 
2003 Vagelos
Email: 
megamatt@sas.upenn.edu
Phone: 
215-746-4738
Admin Support: 
Education: 

B.S., Chemistry, Miami University (2005)

 

Ph.D., Chemistry, The Pennsylvania State University (2011)

 

Merck Helen Hay Whitney Postdoctoral Fellow (2012–2015) and postdoctoral associate (2015–2017), Department of Molecular Medicine, The Scripps Research Institute

Research Interests: 

Research in the Matthews group unites enzymology and chemical biology to develop novel chemical proteomics technologies for the discovery of enzyme cofactors and regulatory post-translational modifications that cannot readily be predicted by gene or protein sequence.

 

Intrinsic nucleophiles abound among the proteinogenic amino acids, but, interestingly, reactive electrophiles are essentially absent. Therefore, the majority of chemical probes target nucleophilic sites to discover enzymes, inhibitors and drug therapies. However, by acquiring them through post-translational modifications, enzymes do indeed exploit diverse classes of protein-bound electrophiles for catalysis and other essential functions. Owing to this mode of acquisition, functional electrophiles are not generally predictable from sequence; thus, their breadth and prevalence remain to be found. Our group is exploring this unknown to understand the functions of reactive modifications that we have found unexpectedly on drug targets implicated in cancer and Alzheimer’s disease. Such discoveries can be uncovered using the ‘reverse-polarity’ chemical probes that we develop. We expect that this largely un-profiled half of the reactive proteome – the covalent ‘electrophilome’ – will be found to rival its 'nucleophilome' counterpart in functional diversity and disease relevance.

Selected Publications: 

The Scripps Research Institute

17.    Matthews ML*, He L, Olson EJ, Horning BD, Correia BE, Yates JR, III, Dawson PE & Cravatt BF*. “Chemoproteomic profiling and discovery of protein electrophiles in human cells.” Nat. Chem. 9, 234–243 (2017).

16.    Horning BD, Suciu RM, Ghadiri D, Ulanovskaya O, Matthews ML, Lum KM, Backus KM, Brown SJ, Rosen H & Cravatt BF. “Chemical proteomic profiling of human methyltransferases.” J. Am. Chem. Soc. 138, 13335–13343 (2016).

15.    Rajagopalan S, Wang C, Yu K, Kuzin AP, Richter F, Lew S, Miklos AE, Matthews ML, Seetharaman J, Su M, Hunt JF, Cravatt BF & Baker D. “Design of activated serine-containing catalytic triads with atomic-level accuracy.” Nat. Chem. Biol. 10, 386-391 (2014).

14.    Chang JW, Niphakis MJ, Lum KM, Cognetta AB, Wang C, Matthews ML, Niessen S, Buczynski MW, Parsons LH & Cravatt BF. “Highly selective inhibitors of monoacylglycerol lipase bearing a reactive group that is bioisosteric with endocannabinoid substrates.” Chem. Biol. 19, 579-588 (2012).

The Pennsylvania State University

13.    Srnec M, Wong SD, Matthews ML, Krebs C, Bollinger JM, Jr. & Solomon EI. “Electronic structure of the ferryl intermediate in the a-ketoglutarate dependent non-heme iron halogenase SyrB2: Contributions to H-atom abstraction reactivity.” J. Am. Chem. Soc. 138, 5110-5122 (2016). 

12.    Matthews ML*, Chang WC, Layne AP, Miles LA, Krebs C & Bollinger JM, Jr.* “Direct nitration and azidation of aliphatic carbons by an iron-dependent halogenase.” Nat. Chem. Biol. 10, 209-215 (2014).  

11.    Wong SD, Srnec M, Matthews ML, Liu LV, Kwak Y, Park K, Bell CB, Alp EE, Zhao JY, Yoda Y, Kitao S, Seto M, Krebs C, Bollinger JM, Jr. & Solomon EI. “Elucidation of the Fe(IV)=O intermediate in the catalytic cycle of the halogenase SyrB2.” Nature 499, 320-323 (2013).

10.    Krebs C, Dassama LMK, Matthews ML, Jiang W, Price JC, Korboukh V, Li N & Bollinger JM, Jr. “Novel approaches for the accumulation of oxygenated intermediates to multi-millimolar concentrations.” Coord. Chem. Rev. 257, 234-243 (2013).

9.      Hollenhorst MA, Bumpus SB, Matthews ML, Bollinger JM, Jr. Kelleher NL & Walsh CT. “The nonribosomal peptide synthetase enzyme DdaD tethers N(b)-fumaramoyl-L-2,3-diaminopropionate for Fe(II)/a-ketoglutarate-dependent epoxidation by DdaC during dapdiamide antibiotic biosynthesis.” J. Am. Chem. Soc. 132, 15773-15781 (2010).

8.      Bollinger JM, Jr. & Matthews ML. “Remote enzyme microsurgery.” Science 327, 1337-1338 (2010).

7.      Matthews ML, Neumann CS, Miles LA, Grove TL, Booker SJ, Krebs C, Walsh CT & Bollinger JM, Jr. “Substrate positioning controls the partition between halogenation and hydroxylation in the aliphatic halogenase, SyrB2.” Proc. Natl. Acad. Sci. USA 106, 17723-17728 (2009).

6.      Matthews ML, Krest CM, Barr EW, Vaillancourt FH, Walsh CT, Green MT, Krebs C & Bollinger JM, Jr. “Substrate-triggered formation and remarkable stability of the C–H bond-cleaving chloroferryl intermediate in the aliphatic halogenase, SyrB2.” Biochemistry 48, 4331-4343 (2009).

5.      Bollinger JM, Jr., Diao Y, Matthews ML, Xing G & Krebs C. “Myo-inositol oxygenase: a radical new pathway for O2 and C-H activation at a nonheme diiron cluster.” Dalton Trans. 905-914 (2009).

4.      Krebs C, Matthews ML, Jiang W & Bollinger JM, Jr. “AurF from Streptomyces thioluteus and a possible new family of manganese/iron oxygenases.” Biochemistry 46, 10413-10418 (2007).

3.      Fujimori DG, Barr EW, Matthews ML, Koch GM, Yonce JR, Walsh CT, Bollinger JM, Jr., Krebs C & Riggs-Gelasco PJ. “Spectroscopic evidence for a high-spin Br-Fe(IV)-oxo intermediate in the a-ketoglutarate-dependent halogenase CytC3 from Streptomyces.”  J. Am. Chem. Soc. 129, 13408-13409 (2007).

 

Miami University, 2001–2005

2.      Matthews ML, Periyannan G, Hajdin C, Sidgel TK, Bennett B & Crowder MW. “Probing the reaction mechanism of the D-ala-D-ala dipeptidase, VanX, by using stopped-flow kinetic and rapid-freeze quench EPR studies on the Co(II)-substituted enzyme.” J. Am. Chem. Soc. 128, 13050-13051 (2006).

1.      Breece RM, Costello A, Bennett B, Sigdel TK, Matthews ML, Tierney DL & Crowder MW. “A five-coordinate metal center in Co(II)-substituted VanX.” J. Biol. Chem. 280, 11074-11081 (2005).

Chemistry Biophysics Mini-Symposium

Fri, 2016-12-09 (All day)
Speaker: 
TBA
Location: 
TBA

Sergei Vinogradov

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First Name: 
Sergei
Last Name: 
Vinogradov
Official Title: 
Associate Professor of Biochemistry and Biophysics

Biophysical Chemistry, Photochemistry/Photophysics

Contact Information
Email: 
VINOGRAD@MAIL.MED.UPENN.EDU
Phone: 
215-573-7524
Education: 

M.S. (Chemistry) Moscow State University, Russia, 1988.

Ph.D. (Organic Chemistry) Moscow State University, Russia, 1995.

Research Interests: 
Dr. Vinogradov's research is focused on the development of advanced probes for microscopy and imaging applications. On the fundamental level our interests encompass chemistry of porphyrins and other pyrrolic dyes, energy and electron transfer in multichromophoric systems, spectroscopy and imaging. Essentially, we are a group of synthetic and physical chemists developing new techniques for biomedical research. Over the past years the main focus of the lab has been optical imaging of oxygen in biological systems, including chemistry of imaging probes, phosphorescence lifetime imaging instrumentation, image reconstruction methods and a variety of applications of phosphorescence. Other bio-analytes of interests have been pH and metal ions. Currently the laboratory also pursues interests in optical energy upconversion and magnetic field effects on luminescence in view of their applications in imaging. Dr. Vinogradov collaborates broadly with laboratories across the world whose interests include basic studies of cellular metabolism and applications in neuroscience, stem cell biology, cancer therapy, tissue engineering and ophthalmology.
Selected Publications: 

Esipova, T. V., Ye, X. C., Collins, J. E., Sakadzic, S., Mandeville, E. T., Murray, C. B., Vinogradov, S. A.: Dendritic upconverting nanoparticles enable in vivo multiphoton microscopy with low-power continuous wave sources. PNAS 109(51): 20826-20831, 2012.

 

Mani, T., Tanabe, M., Yamauchi, S., Tkachenko, N. V., Vinogradov, S. A.: Modulation of Visible Room Temperature Phosphorescence by Weak Magnetic Fields. Journal of Physical Chemistry Letters 3(21): 3115-3119, 2012.

 

Mani, T., Niedzwiedzki, D.M., Vinogradov, S.A.: Generation of Phosphorescent Triplet States via Photoinduced Electron Transfer: Energy and Electron Transfer Dynamics in Pt Porphyrin-Rhodamine B Dyads. J. Phys. Chem. A. 116: 3598−3610, 2012.

 

Vinogradov, S.A., Wilson, D.F. : Porphyrin-dendrimers as biological oxygen sensors. Designing dendrimers. Wiley, 2012.

 

Esipova, T. V., Karagodov, A., Miller, J., Wilson, D. F., Busch, T. M., Vinogradov, S. A.: Two new "protected" oxyphors for biological oximetry: properties and application in tumor imaging. Analytical Chemistry 83(22): 8756-8765, 2011.

 

Lecoq, J., Parpaleix, A., Roussakis, E., Ducros, M., Houssen, Y. G., Vinogradov, S. A.*, Charpak, S.*: Simultaneous two-photon imaging of oxygen and blood flow in deep cerebral vessels. Nature Medicine 17(7): 893-U262, 2011 Notes: Note that postdoc E. Roussakis is a co-first author and I am one of the two senior corresponding authors. My lab is entirely responsible for the new oxygen microscopy technology and worked with the collaborator to implement it in the brain.

 

Finikova, O. S., Lebedev, A. Y., Aprelev, A., Troxler, T., Gao, F., Garnacho, C., Muro, S., Hochstrasser, R. M., Vinogradov, S. A.: Oxygen microscopy by two-photon-excited phosphorescence. ChemPhysChem 9(12): 1673-1679, 2008.

 

Apreleva, S. V., Wilson, D. F., Vinogradov, S. A.: Tomographic imaging of oxygen by phosphorescence lifetime. Applied Optics 45(33): 8547-8559, 2006.

Jessica M. Anna

Photo: 
First Name: 
Jessica M.
Last Name: 
Anna
Official Title: 
Assistant Professor of Chemistry

Physical Chemistry, Laser Spectroscopy, Ultrafast Dynamics, Chemical Reaction Dynamics, and Energy Science

Additional Titles: 
Elliman Faculty Fellow
Contact Information
Office Location: 
251 Chem
Email: 
jmanna@sas.upenn.edu
Phone: 
215-746-2354
Admin Support: 
Education: 

B.S. University of Pittsburgh (2006)

 

Ph.D. University of Michigan (2011)

 

Postdoctoral Research Fellow, University of Michigan (2011)

 

Postdoctoral Research Fellow, University of Toronto (2011-2014)

Research Interests: 

Solar energy conversion, in both natural and artificial systems, involves the absorption of a photon that can then lead to a series of energy and electron transfer events. Research in the Anna group focuses on understanding these photoinitiated processes. More specifically we are interested in exploring (1) the interplay of vibrational motion with both electronic energy transfer and electron transfer reactions, and (2) the role the environment plays in these processes. To begin to answer these questions we employ both well-established and novel multidimensional spectroscopic techniques to explore photoinitiated processes in a range of systems, spanning interests in biology, chemistry, and physics.

Selected Publications: 

J. M. Anna, M. R. Ross, K. J. Kubarych, “Dissecting Enthalpic and Entropic Barriers to Ultrafast Equilibrium Isomerization of a Flexible Molecule Using 2DIR Chemical Exchange Spectroscopy”, J. Phys. Chem. A 113 (2009) 6544-6547.

 

J. M. Anna and K. J. Kubarych, “Watching Solvent Friction Impede Ultrafast Barrier Crossings: A Direct Test of Kramers Theory”, J. Chem. Phys. 133 (2010) 174596.

 

J. M. Anna, M. J. Nee, C. R. Baiz, R. McCanne, K. J. Kubarych, “Measuring Absorptive Two-Dimensional Infrared Spectra Using Chirped-Pulse Upconversion Detection”, J. Opt. Soc. Am. B. 27 (2010) 382-393.

 

J. M. Anna, E. E. Ostroumov, K. Maghlaoui, J. Barber, and G. D. Scholes “Two-Dimensional Electronic Spectroscopy Reveals Ultrafast Downhill Energy Transfer in Photosystem I Trimers of the Cyanobacterium Thermosynechococcus elongatus”, J. Phys. Chem. Lett. (2012), 3, 3677-3684.

 

J. M. Anna, Y. Song, R. Dinshaw and G. D. Scholes “Two-dimensional electronic spectroscopy for mapping photophysics”, Pure. Appl. Chem. (2013), 85, 1307-1319.

 

J. M. Anna, G. D. Scholes, and R. van Grondelle, “A Little Coherence in Photosynthetic Light Harvesting”, BioScience (2014), 64, 14-25

Elizabeth Rhoades

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First Name: 
Elizabeth
Last Name: 
Rhoades
Official Title: 
Associate Professor of Chemistry
Contact Information
Office Location: 
258 Chemistry Building
Email: 
elizabeth.rhoades@sas.upenn.edu
Phone: 
215-573-6477
Fax: 
215-573-2112
Admin Support: 
Education: 
  • postdoctoral associate with Professor Watt Webb at Cornell University (2003-2006)
  • postdoctoral associate with Professor Gilad Haran at the Weizmann Institute of Science (2001-2003)
  • PhD in Biophysics from the University of Michigan, Ann Arbor (2001)
  • B.S. in Physics from Duke University (1994)
Research Interests: 

Research in the Rhoades lab aims to elucidate the principles that link protein conformational change with structure-function relationships, focusing on understanding structural plasticity in intrinsically disordered proteins (IDPs). IDPs do not form stable structures under physiological conditions; for many, function is dependent upon disorder. This is in striking contrast to the structure-function paradigm that dominates our understanding of globular proteins. Given the large fraction of the eukaryotic proteome predicted to be disordered, the scope of the problem and the need for new insights are enormous.

 

Much of our effort is directed towards IDPs whose aggregation is central to the pathology of several degenerative diseases: α-synuclein (Parkinson’s disease), tau (Alzheimer’s disease), and IAPP (Type II Diabetes). These three proteins have diverse native functions and binding partners, but share intriguing commonalities of toxic mechanism and the importance of templated selfassembly. Studying systems in parallel allows us to generate protein and disease-specific insights as well as determine principles relevant to general functional and dysfunctional mechanisms of IDPs.

 

Our primary approaches center on single molecule optical techniques. These approaches enable quantitative and structural assessments of our systems in isolation and in the context of biologically relevant interactions. Single molecule approaches are unique in their ability to characterize systems which exist and function as a dynamic ensemble of states.

Selected Publications: 

1.      X.-H. Li, J. A. Culver, and E. Rhoades (2015) “Tau binds to multiple tubulin dimers with helical structure” Journal of the American Chemical Society, 137: 9218-921


2.     A. Nath, D. E. Schlamadinger, E. Rhoades, and A.D. Miranker (2015) “Structure-based small molecule modulation of a pre-amyloid state: pharmacological enhancement of IAPP membrane-binding and toxicity” Biochemistry, 349: 54-58

3.     D. Jülich, G. Cobb,  A.M. Melo, P. McMillen, A. Lawton,  S.G.J. Mochrie, E. Rhoades, and S.A. Holley (2015) “Cross-scale Integrin regulation organizes ECM and tissue topology” Developmental Cell, 34: 33-44

4.     J. LaRochelle, G. Cobb, A. Steinauer, E. Rhoades, and A. Schepartz (2015) “Fluorescence correlation spectroscopy revealsy highly efficient endosomal escape by certain penta-arg proteins and stapled peptides” Journal of the American Chemical Society. 127: 2536-2541 January 2015

5.     S.Kumar, D.E. Schlamadinger, M.A. Brown, J.M. Dunn, B. Mercado, J.A. Hebda, I Saraogi, E. Rhoades, A.D. Hamilton, and A.D. Miranker (2014) “IAPP and the shared molecular origins of leakage and toxicity” Chemistry and Biology, 19: 369-378

6.     A.R. Braun, M.M. Lacy, V.C. Ducas, E. Rhoades, and J.N. Sachs (2014) “α-Synuclein-induced membrane remodeling is driven by binding affinity, partition depth, and interleaflet order asymmetry” Journal of the American Chemical Society, 136: 9962-9972

7.  S. Elbaum-Garfinkle, G. Cobb, J. T. Compton, X. Li and E. Rhoades (2014)“Tau mutants bind tubulin heterodimers with enhanced affinity” Proceedings of the National Academy of Sciences U.S.A., 111: 6311-6316

8.  D. C. DeWitt and E. Rhoades (2013) “α-Synuclein Inhibits SNARE-mediated Vesicle Fusion Through Direct Interactions with Lipid Bilayer” Biochemistry, 52: 2385-2387

9.  B. R. Capraro, Z. Shi, J.M. Dunn, T. Wu, E. Rhoades, and T. Baumgart (2013) “Kinetics of endophilin N-BAR domain dimerization and membrane interactions” Journal of Biological Chemistry, 288: 12533-12543

10.  S. Elbaum-Garfinkle and E. Rhoades (2012) “Long-Range Interactions Modulate Aggregation of Tau by Altering the Conformational Ensemble” Journal of the American Chemical Society, 134: 16607-16613

11.     A. Nath, M. Sammalkorpi, D. DeWitt, A.J. Trexler, S. Elbaum-Garfinkle, C.S. O’Hern and  E. Rhoades (2012) “The Conformational Ensembles of  α-Synuclein and Tau:  Combining Single-Molecule FRET and Simulations”  Biophysical Journal, 103: 1940-1949

12.     V. Ducas and E. Rhoades (2012) “Quantifying β-Synuclein and g-Synuclein Membrane Interactions”  Journal of Molecular Biology, 423:528-539

13.     A.J. Trexler and E. Rhoades  (2012) “N-terminal acetylation is critical for forming α-helical oligomer of α-Synuclein” Protein Science, 21:601-605  

14.     A.R. Braun, E. Sevcsik, P. Chin, E. Rhoades, S. Tristram-Nagle, and J.N. Sachs (2012) “α-Synuclein Induces Both Positive Mean Curvature and Negative Gaussian Curvature in Membranes” Journal of the American Chemical Society,  134: 2613-2620  

15.     A. Nath, A. D. Miranker, and E. Rhoades (2011) “A Membrane-bound Dimer of Islet Amyloid  Polypeptide Studied by Single-Particle FRET”  Angewandte Chemie, 50: 10859-10862   
   
16.     N.B. Last, E. Rhoades, and A.D. Miranker (2011) “Islet Amyloid Polypeptide Demonstrates A Persistent Capacity to Disrupt Membrane Integrity” Proceedings of the National Academy of Sciences, U.S.A., 108: 9460-9465   

17.     E. Sevcsik, A.J. Trexler, J.M. Dunn, and E. Rhoades (2011) “Allostery in a disordered protein: Oxidative modifications to α-Synuclein act distally to regulate membrane binding” Journal of the American Chemical Society, 133: 7152-7158  

18.  A.J. Trexler and E. Rhoades (2010) “Single molecule characterization of α-Synuclein in aggregation-prone states” Biophysical Journal, 99: 3048-3055    

19.  E. R. Middleton and E. Rhoades (2010) “Effects of vesicle curvature and composition on α-Synuclein binding to lipid vesicles” Biophysical Journal, 99: 2279-2288  

20.  A . J. Trexler and E. Rhoades (2009) “α-Synuclein binds large unilamellar vesicles as an extended helix”Biochemistry, 48: 2304-2306  

Jeffery G. Saven

Photo: 
First Name: 
Jeffery G.
Last Name: 
Saven
Official Title: 
Professor of Chemistry

Biological and Theoretical Physical Chemistry

Contact Information
Office Location: 
266 Cret, Lab 261 Cret
Email: 
saven@sas.upenn.edu
Phone: 
215-573-6062
Fax: 
215-573-2112
Admin Support: 
Education: 
  • BA, New College of Florida
  • PhD, Columbia University & University of Wisconsin
  • NSF Postdoctoral Fellow in Chemistry, University of Illinois, Urbana-Champaign, 1993-1995. Postdoctoral Research Associate, University of Illinois, Urbana-Champaign, 1995-1997
Research Interests: 

Computationally designed protein complex containing a nonbiological cofactor, designed and studied in collaboration with the DeGrado and Therien groups in the Department of Chemistry. On the left is the computationally designed protein scaffold (magenta) and two abiotic porphyrin cofactors (yellow). On the right is a model of the computationally designed sequence and structure.

 

Our research interests involve theoretical chemistry, particularly as it applies to biopolymers, macromolecules, condensed phases, and disordered systems. We are developing computational methods for understanding and designing molecular sytems having many physical and chemical degrees of freedom. Molecular simulation techniques are used both to study molecular systems in detail and to test and illustrate our theories. 

 

A current thrust of the group involves developing computational tools for understanding the properties of protein sequences consistent with a chosen three-dimensional structure. The group works closely with experimental groups at Penn and at other universities; some group members are involved in joint theoretical/experimental projects. Recent projects involve the design of soluble and membrane bound proteins, discerning the origins of conservation in naturally occurring proteins, biomolecular simulation, and the design of nonbiological folding molecules.

Ronen Marmorstein

Photo: 
First Name: 
Ronen
Last Name: 
Marmorstein
Official Title: 
Professor, Department of Biochemistry and Biophysics Investigator, Abramson Family Cancer Research Institute

Biological Chemistry

Additional Titles: 
Wistar Institute Professor of Chemistry
Contact Information
Office Location: 
BRB II/III, Room 454
Email: 
marmor@mail.med.upenn.edu
Phone: 
215-898-7740
Fax: 
215-746-5511
Education: 
  • B.S. University of California at Davis (1984)
  • M.S. University of Chicago (1989)
  • Ph.D. University of Chicago (1989)
  • Postdoctoral Fellow, Harvard University (1989-1994)
Research Interests: 

The laboratory uses a broad range of molecular, biochemical and biophysical research tools centered around X-ray crystal structure determination to understand the mechanism of chromatin recognition and assembly and post-translational histone and protein modification in the regulation of gene expression; and kinase signaling pathways. The laboratory is particularly interested in gene regulatory proteins and their upstream signaling kinases that are aberrantly regulated in cancer and age-related metabolic disorders such as type II diabetes and obesity, and the use of high-throughput small molecule screening and structure-based design strategies towards the development of protein-specific small-molecule probes to be used to further interrogate protein function and for development into therapeutic agents.

Chromatin recognition and assembly and histone modification in gene regulation. DNA within the eukaryotic nucleus is compacted into chromatin containing histone proteins and its appropriate regulation orchestrates all DNA-templated reactions such as DNA transcription, replication, repair, mitosis, and apoptosis. Among the many proteins that regulate chromatin, the proteins that recognize DNA, assemble chromatin, called histone chaperones, and that modify the histones through the addition or removal of functional groups such as acetyl, methyl or phosphate play important roles. We are studying the DNA binding proteins p53, FoxO and the Gal4 family; the histone chaperones HIRA, Asf1, Vps75 and their associated factors; and the family of histone acetyltransferase (HAT) and histone deacetylase (HDAC) enzymes. We are particularly interested in how DNA binding proteins navigate the recognition of their cognate DNA targets, how histone chaperones coordinate the assembly of distinct chromatin complexes correlated with different DNA regulatory processes, and how histone modification enzymes link catalysis to their substrate specific activities for their respective biological activities. More recently, we have been studying how the binding of accessory and regulatory protein subunits regulates the various activities of these proteins and in some cases we are developing small molecule protein specific inhibitors.

 

Enzymes associated with aging and age-related disorders.Sirtuin enzymes are NAD+-dependent histone and protein deactylases and/or ADP-ribotransferases that have been implicated in the regulation of gene expression, cellular aging, adipogenesis, type II diabetes and several neurodegenerative disorders. We have determined the structure of these enzymes in several liganded forms and have developed novel small molecule sirtuin inhibitors. Together with associated biochemical studies, these studies have provided insights into the mode of catalysis and substrate-specific recognition by this protein family and have illuminated new avenues for small molecule effector design. We are currently working towards understanding the factors that distinguish different sirtuin proteins and how the functions of these proteins are modulated by other protein factors. We are also pursuing structure/function studies of other proteins that are implicated in aging and age-related disorders.

 

Tumor suppressors and oncoproteins. We are carrying out biochemical and structural studies on the tumor suppressor proteins pRb, p53 and p300/CBP, both alone and in complex with their relevant protein targets. We are also interested in the mode of inactivation of these tumor suppressors by the viral oncoproteins E7 and E6 from human papillomavirus (HPV), the etiological agent for cervical cancer, and Adenovirus (Ad) E1A. We are also combining structural studies with small molecule screening to prepare small molecule HPV-E7 and for HPV-E6 inhibitors. Most recently we have begun to exploit structure-based design strategies to develop inhibitors of oncogenic kinases, such as PI3K, BRAF and PAK1 implicated in melanoma and other cancers. Our goal for these studies is to derive functional and structural information that will lead to the design of small molecule compounds that may have therapeutic applications.

Tumor suppressors and viral oncoproteins- We are pursuing biochemical and structural studies on the tumor suppressor proteins p18INK4c, pRb, p53 and p300/CBP, both alone and in complex with their relevant protein targets. The activity of pRb is inhibited by several known DNA viral oncoproteins, including human papillomavirus (HPV) E7, the etiological agent for cervical cancer, and Adenovirus (Ad) E1A. We have most recently characterized the binding properties of pRb to HPV-E7 and Ad-E1a and are now determining their structures both alone and in complex with pRb. Our goal for these studies is to derive functional and structural information that will lead to the design of small molecule compounds that may have clinical applications against cancer.

 

Protein-DNA recognition- As a model to understand sequence-specific DNA recognition by transcriptional regulatory proteins, we are studying the structure and function of three families of DNA binding proteins, the fungal specific Zn2Cys6 binuclear cluster proteins, the higher eukaryotic Ets proteins and p53. We have determined several structures of these proteins either alone or in complex with their associated DNA targets and are continuing to use these proteins as a model to understand DNA recognition by protein and protein complexes. With regard to p53, we are studying its unique mode of DNA recognition and are developing structure-based strategies for the repair of tumor-derived p53 mutations.

Other Affiliations: 

Andrea J. Liu

Photo: 
First Name: 
Andrea J.
Last Name: 
Liu
Official Title: 
Hepburn Professor of Physics
Additional Titles: 
Professor of Chemistry
Contact Information
Office Location: 
2N30, David Rittenhouse Laboratory
Email: 
ajliu@physics.upenn.edu
Phone: 
(215) 573-7374
Fax: 
(215) 898-2010
Education: 

Ph.D., Cornell University (1989)
B.A., University of California, Berkeley (1984)

Research Interests: 

In my research group, we use a combination of analytical theory and numerical simulation to study problems in soft matter physics ranging from jamming in glassforming liquids, foams and granular materials, to biophysical self-assembly in actin structures and other systems. The idea of jamming is that slow relaxations in many different systems, ranging from glassforming liquids to foams and granular materials, can be viewed in a common framework. For example, one can define jamming to occur when a system develops a yield stress or extremely long stress relaxation time in a disordered state. According to this definition, many systems jam. Colloidal suspensions of particles are fluid but jam when the pressure or density is raised. Foams and emulsions (concentrated suspensions of deformable bubbles or droplets) flow when a large shear stress is applied, but jam when the shear stress is lowered below the yield stress. Even molecular liquids jam as temperature is lowered or density is increased this is the glass transition. We have been testing the speculation that jamming has a common origin in these different systems, independent of the control parameter varied. On the biophysical side, our research has been motivated recently by the phenomenon of cell crawling. When a cell crawls, its cytoskeleton--a network of filaments (primarily composed of the protein actin) that maintains the mechanical rigidity of the cell and gives the cell its shape--must reorganize in structure. This reorganization is accomplished via polymerization, depolymerization and branching of actin filaments, as well as by crosslinking the filaments together with "linker" proteins. The morphology of the resulting structure is of special interest because it determines the mechanical properties of the network. We are developing dynamical descriptions that capture morphology. In addition, we are exploring models for how actin polymerization gives rise to force generation at the leading edge.

Zahra Fakhraai

Photo: 
First Name: 
Zahra
Last Name: 
Fakhraai
Official Title: 
Associate Professor of Chemistry

Physical Chemistry, Materials Chemistry, Nanoscale Science and Engineering

Contact Information
Email: 
fakhraai@sas.upenn.edu
Admin Support: 
Education: 
  • B.Sc. Physics, Sharif University of Technology, Iran 1999
  • M. Sc. Physics, Sharif University of Technology, Iran 2001
  • Ph.D. Physics, University of Waterloo, 2007
  • Post-Doctoral associate, Chemistry, University of Toronto, 2007-08.
  • NSERC Post-Doctoral Fellow, Chemistry, University of Wisconsin-Madison, 2009-11.
Research Interests: 

Our group is interested to study the effect of nano-confinement on structure, dynamics and other properties of materials. Materials behave differently on surfaces, interfaces or small length scales compared to their bulk properties.  Understanding such differences are crucial in many technological applications where materials are constrained in nanometer size spaces, such as organic electronics, polymer applications and drug delivery. One can take advantage of such difference to produce novel materials, such asexceptionally stable glasses or harvest light for various applications. In biological systems, most of the dynamics happens in nanometer size proximity of surfaces and interfaces, and understanding the properties in confinement is a key in predicting function. We focus our efforts on understanding the origins of such modified properties on a fundamental level as well as possible application of such phenomena in producing novel materials or experimental tools.


Enhanced Mobility at the Surface of Polymeric and Organic Glasses: 

 

We study the properties of glasses at the air/glass interface. Our studies show that below the glass transition temperature, where the bulk of the material is in an out of equilibrium state, the interfacial dynamics are many orders of magnitude faster that the bulk dynamics. As a result a layer close to the interface maintains equilibrium properties. We study the dynamics of this layer, its thickness, and its effect on the properties of the underlying glass. The interfacial layer can strongly modify properties of amorphous materials in nanometer length scales. They also allow one to produce near-equilibrium structures at temperatures well below bulk glass transition temperature, through physical vapor deposition.


Exceptionally Stable Glasses: 


 

The enhanced mobility of the interfacial layer allows us to produce near-equilibrium glasses at temperatures well below the bulk glass transition temperature, Tg, by means of physical vapor deposition (PVD). Exceptionally stable glasses are formed when the substrate temperature during PVD is maintained just below the glass transition temperature. We study the morphology and the kinetics of PVD films during formation and their relationship to the final properties of the stable glass. These studies provide information on mechanisms of rapid aging below Tg and stable glass formation. We also investigate exceptional material properties of these glasses and the role of the chemical structure in these properties such as the optical birefringence and electronic properties.


 

Novel Emergent Optical Properties in Disordered Nanoparticle Clusters: 


 

Using simple synthetic routs we can produce dielectric core-gold shell nanoparticles decorated with randomly packed nanoparticles of various shapes and sizes. Spiky nanoparticles are a good example of such nanoparticles. Broadband and tunable structure of spiky gold nanoshells makes them ideal for various applications such as enhanced Raman scattering, temperature and index sensing and sensors for biological and light harvesting applications. Exceptional properties, such as higher order quadrupoloar scattering and magnetic dipole plasmons in these nanoparticles are due to inherent disorder in their structure and random packing arrangements. We explore optical properties of these nanoshells, using various theoretical and experimental tools. We also develop new techniques that allow us to study properties of meta materials formed from these types of particles.

 


Surface Mediated Self-assembly of Amyloid Aggregrates: 


 

Surface self-assembly provides an alternative pathway for amyloid aggregation that is not available in bulk solutions. We us high-resolution atomic force microscopy and other imaging techniques to study the adhesion and diffusion of peptides on various surfaces and their role in facilitating amyloid fibril formation through self-assembly routs. We also use our exceptional capabilities in high-resolution imaging to study the conformation of amyloids formed under various conditions in aqueous conditions.

Selected Publications: 

1.     T. Liu, K. Cheng, E. Salami, F. Gao, C. Li, X. Tong, Y. Lin, Y. Zhang, W. Zhang, L. Klinge, P. Walsh and Z. Fakhraai, "The effect of chemical structure on the stability of physical vapor deposited glasses of 1,3,5-triarylbenzene"J. Chem. Phys. 143, 084506 (2015). 

2.     Z. Qian, S.P. Hastings, C. Li, B. Edward, C.K. McGinn, N. Engheta, Z. Fakhraai* and S.J. Park, "Raspberry-like Metamolecules Exhibiting Strong Magnetic Resonances",  ACS Nano9, 1263-1270 (2015). 

3.     E. Glor, and Z. Fakhraai, "Facilitation of Interfacial Dynamics in Entangled Polymer Films", J. Chem. Phys. 141, 194505 (2014).

4.     Y. Lin, E.J. Peterson, and Z. Fakhraai, "Surface Effects Mediate Self-Assembly of Amyloid-β Peptides"ACS Nano8, 10178-10186 (2014).

5.     S. P. Hastings, P. Swanglap, Z. Qian, Y. Fang, S.J. Park, S. Link, N. Engheta, and Z. Fakhraai, "Quadrupole-Enhanced Raman Scattering", ACS Nano,  8 , 9025-9034 (2014).

6.     B. Sanchez-Gaytan, Z. Qian, S. Hastings, M. Reca, Z. Fakhraai, and S. J. Park, “Controlling
the Topography and Surface Plasmon Resonance of Gold Nanoshells by a Templated Surfactant-Assisted Seed Growth Method
 ”, J. Phys. Chem. C. 117, 8916-8923 (2013).

7.     C. R. Daley, Z. Fakhraai, M. D. Ediger, and J. A. Forrest, “Comparing Surface and Bulk Flow of a Molecular Glass Former”, Soft Matter, 8, 2206-2212 (2012). 

8.     M. Paulite, Z. Fakhraai, N. Gunari, A. Tanur, and G. C. Walker, “Imaging Secondary Structure of Individual Amyloid Fibrils of a β(2)-Microglobulin Fragment Using Near-Field Infrared Spectroscopy”, J. Am. Chem. Soc. 133, 7376-7383 (2011).

9.     Z. Fakhraai and J. A. Forrest, “Measuring the Surface Dynamics of Glassy Polymers”, Science, 319, 600- 604 (2008).

10.  Z. Fakhraai, and J. A. Forrest, “Probing Slow Dynamics in Supported Thin Polymer Films”, Phys. Rev. Lett. 95, 025701(2005).

Ivan J. Dmochowski

Photo: 
First Name: 
Ivan J.
Last Name: 
Dmochowski
Official Title: 
Professor of Chemistry

Bioinorganic, Bioorganic, Biophysical Chemistry

Additional Titles: 
Undergraduate Chair
Contact Information
Office Location: 
348 N, Lab: 332, 334, 336, 338 N
Email: 
ivandmo@sas.upenn.edu
Phone: 
215-898-6459
Twitter: 
@DmochowskiUPenn
Admin Support: 
Education: 
  • B.A. Harvard College (1994)
  • Research Fellow, Johannes Gutenberg Universitaet, Mainz, DE (1994-1995)
  • Ph.D. California Institute of Technology (2000)
  • Caltech Herbert Newby McCoy Award (2000)
  • Helen Hay Whitney Postdoctoral Fellow, Biophysics, Caltech (2000-2002)
  • Camille and Henry Dreyfus New Faculty Award (2003)
  • National Science Foundation CAREER Award (2005)
  • Camille and Henry Dreyfus Teacher-Scholar Award (2007)
Research Interests: 

Our lab is developing chemical and biophysical tools to study and manipulate complex biological systems. Projects span many areas of synthetic organic, inorganic, and biophysical chemistry; molecular, cell, and developmental biology; and bioengineering. We are particularly interested in developing new technologies for biomolecular imaging and the fabrication of functional bio-nanomaterials.

Hyperpolarized 129Xe Biosensors for Early Cancer Detection

Molecular imaging technologies hold great promise for early cancer diagnosis and intervention. Our goal is to develop new reagents that extend the capabilities of magnetic resonance imaging (MRI) for monitoring multiple cancer markers simultaneously in vivo. 129Xe has found increasing use for biological imaging applications, due to its biological compatibility (xenon is an anesthetic at high concentrations), hyperpolarizability (this enhances signals 1,000-fold), and high affinity for organic cages such as cryptophanes. The chemical shift of 129Xe varies by a remarkable 200 ppm, depending on its molecular environment: Thus, a 129Xe atom encapsulated inside a cryptophane is a sensitive reporter of perturbations outside the cage. Based on this principle, our lab is generating new biosensors that will identify biomarkers associated with cancers of the breast, lungs, brain, and pancreas. The long-range goal of this project is to use MRI to detect aberrant proteins that cause cancer in humans, years before the formation of a tumor.

Ferritin Templates for Nanoparticle Synthesis and Assembly

The goal of this project is to use ferritin proteins as templates for synthesizing and assembling inorganic nanoparticles with nanometer precision. Ferritins contain 24 four-helix bundle subunits that self-assemble to create a large central cavity. We have made water-stable, 10-12-nm gold and silver nanoparticles inside ferritin (gray sphere). Particles are fully characterized using facilities at the UPenn Laboratory for Research on the Structure of Matter (LRSM). We are functionalizing the surface of these ferritin-metal nanoparticles for sensing and nano/biomaterials applications. We are also performing computational protein design, in collaboration with the Saven lab, to mutate residues inside the ferritin cavity to enhance their metal-binding properties. Methods for organizing ferritin metal nanoparticles in 2- and 3-dimensions are being developed, in order to build very small conducting circuits. 

Laser-Activated Chemical Biology: Controlling Genes with Light

The goal of this project is to develop methods for turning genes "on" and "off" with light inside neurons and developing zebrafish embryos with high spatial and temporal control. As a first step, we have developed methods for incorporating a photoactive blocking group in the middle of a DNA or RNA oligonucleotide. In one application, we modulated primer extension by DNA polymerase (KF) using UV light. Photoactivation was monitored using a fluorescent reporter. We are now developing methods to control protein translation by the ribosome using similarly caged RNA. Blocking groups mask the messenger RNA start codon, and are designed to prevent translation until photocleavage. We will control complex gradients of proteins involved in cell signaling during zebrafish development and wound healing, using a state-of-the-art UV confocal microscope in the lab.

Selected Publications: 

 

X. Tang, J. Swaminathin, A.M. Gewirtz, I.J. Dmochowski, Regulating gene expression in human leukemia cells using light-activated oligodeoxynucleotides, Nucl. Acids Res. (36) 559-569, 2008.

 

J.A. Aaron, J.M. Chambers, K.M. Jude, L. Di Costanzo, I.J. Dmochowski, D.W. Christianson, Structure of a 129Xe-cryptophane biosensor complexed with human carbonic anhydrase II, J. Am. Chem. Soc. (130) 6942-6943, 2008.

 

G.K. Seward, Q. Wei, I.J. Dmochowski, Peptide-mediated cellular uptake of cryptophane, Bioconjug. Chem. (19) 2129-2135, 2008.

 

J.L. Richards, X. Tang, A. Turetsky, I.J. Dmochowski, RNA bandages for photomodulating in vitro protein synthesis, Bioorg. Med. Chem. Lett. (18) 6255-6258, 2008.

 

C. Butts, J. Swift, S.-G. Kang, L. Di Costanzo, D.W. Christianson, J.G. Saven, I.J. Dmochowski, Directing noble metal ion chemistry within a designed ferritin protein, Biochemistry (47) 12729-12739, 2008.

 

J.L. Chambers, P.A. Hill, J.A. Aaron, Z. Han, D.W. Christianson, N.N. Kuzma, I.J. Dmochowski, Cryptophane xenon-129 nuclear magnetic resonance biosensors targeting human carbonic anhydrase, J. Am. Chem. Soc. (131) 563-569, 2009.

 

P.A. Hill, Q. Wei, T. Troxler, I.J. Dmochowski, Substituent effects on xenon binding affinity and solution behavior of water-soluble cryptophanes, J. Am. Chem. Soc. (131) 3069-3077, 2009.

 

G.P. Robbins, M. Jimbo, J. Swift, M.J. Therien, D.A. Hammer, I.J. Dmochowski, Photo-initiated destruction of composite porphyrin-protein polymersomes, J. Am. Chem. Soc., (131) 3872-3874, 2009. 

 

J. Swift, C. Butts, J. Cheung-Lau, V. Yerubandi, I.J. Dmochowski, Efficient self-assembly of Archaeoglobus fulgidus ferritin around metallic cores, Langmuir, (25) 5219-5225, 2009.

 

C.A. Butts, J. Xi, G. Brannigan, M.L. Klein, R.G. Eckenhoff, I.J. Dmochowski, Identification of a fluorescent general anesthetic, 1-aminoanthracene, Proc. Natl. Acad. Sci. U.S.A. (106) 6501-6506, 2009.

 

I.J. Dmochowski, Xenon out of its shell, Nature Chemistry, ‘In Your Element’ invited feature article, vol. 1, 250, June 2009.

 

O. Taratula, I.J. Dmochowski, Functionalized 129Xe contrast agents for magnetic resonance imaging, Curr. Opin. Chem. Biol. (14) 97-104, 2010.

 

J.L. Richards, G.K. Seward, Y. Huang, I.J. Dmochowski, Turning DNAzymes on and off with light, ChemBioChem (11) 320-324, 2010.

 

J. Lampe, Z. Liao, I.J. Dmochowski, P.S. Ayyaswamy, D.M. Eckmann, Imaging macromolecular interactions at an interface, Langmuir (26) 2452-2459, 2010.

Courses Taught: 
  • Chemistry 101, "General Chemistry"
  • Chemistry 559, "Biomolecular Imaging"
  • Chemistry 567, “Bioinorganic Chemistry”

Department of Chemistry

231 S. 34 Street, Philadelphia, PA 19104-6323

215.898.8317 voice | 215.573.2112 fax | web@chem.upenn.edu

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