Biochemistry and Molecular Biophysics Graduate Group

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Yair Argon, Ph.D.

Quality control of protein folding in the cell by molecular chaperones

Professor of Pathology & Laboratory Medicine
Chief, Division of Cell Pathology, Children's Hospital of Philadelphia
816B Abramson Research Center
Tel: 267-426-5131 (office) / 267-426-5130,29,28 (lab) / 267-426-5346 (administrator)
Fax: 267-426-5165
CHOP website

Orchestrating protein folding in the cell is a key process underlying the expression of membrane receptors and secreted proteins. Inefficient folding leads to inappropriate protein-protein interactions, inability to transport proteins from the ER to the Golgi complex, and is the molecular basis of many diseases. The molecular chaperones in the ER govern proper folding and assembly, recognize misfolded proteins and either improve folding or direct them to degradation. Our work focuses on two molecular chaperones, BiP and GRP94.


Paul H. Axelsen, M.D.

Protein misfolding diseases and pathological protein-lipid interactions; rational drug design

Professor of Pharmacology, Biochemistry & Biophysics, and Medicine
1009C Stellar-Chance Labs
Tel: (215) 898-9238
Lab website

Millions of dollars, thousands of investigators, and decades of effort, have not yet answered increasingly urgent questions about the cause of sporadic late-onset Alzheimer's disease, or what to do about it. The seemingly intractable nature of this problem has prompted the Axelsen laboratory to seek answers outside the mainstreams of thought about Alzheimer's. In doing so, we find compelling reasons to focus on the possibility that this disease is due to pathological protein-lipid interactions induced by oxidative stress. The lab uses a variety of biochemical and biophysical technologies (FTIR, 2D-IR, Mass Spec, fluorescence, custom-synthesized radiotracers) to explore these pathogenic mechanisms and gauge the effects of potential therapeutic interventions.


Tobias Baumgart, Ph.D.

Biomembrane function: thermodynamics, dynamics and mechanics

Associate Professor of Chemistry
250N Chemistry 1973 Wing
Tel: 215-573-7539 / Fax: 215-898-6242
Lab website

Among the most fascinating biological structures found in nature are biomembranes that surround cellular systems and intracellular organelles. These membranes function as barriers between cellular compartments, as transport vehicles and regulators, and contain machineries important for biological functioning. Cell biology has traditionally focused on examining protein / protein interactions. However, the physical chemistry and mechanical properties of the lipid bilayer matrix are tightly coupled to the functioning of membrane associated proteins in ways that are largely unknown. This provides rich opportunities for exciting and important new insights.

We examine lipid / protein interactions in biological and model membranes by laser scanning confocal microscopy techniques. Membrane domain formation is studied in a temperature-dependent fashion. We are particularly interested in establishing the molecular details that determine how membrane proteins redistribute between lipid domains to understand how lipid / protein interactions influence membrane functioning. Furthermore, we use mechanical methods to deform membranes and examine membrane curvature-dependent lipid / protein interactions that include redistribution in membrane curvature gradients, curvature-dependent binding of peripheral membrane proteins, and we study protein geometries dependent on lipid membrane curvature.


Ben E. Black, Ph.D.

Chromosome segregation; chromatin structure; epigenetic centromere specification; hydrogen/deuterium exchange

Associate Professor of Biochemistry & Biophysics
913A Stellar-Chance Labs
Tel: 215-898-5039 (office) / Fax: 215-573-7058
Lab: 912 Stellar Chance Labs
Tel: 215-898-4476 (lab)
Departmental website

Dr. Black's laboratory is interested in how particular proteins direct accurate chromosome segregation at mitosis. In humans, the chromosomal element—the centromere—that directs this process is not defined by a particular DNA sequence. Rather, the location of the centromere is dictated by an epigenetic mark generated by one or more resident proteins. These centromeric proteins interact directly with the DNA to create a specialized chromatin compartment that is distinct from any other part of the chromosome. By taking biophysical, biochemical, and cell biological approaches, our work is to define the composition and physical characteristics of the protein and protein/DNA complexes that epigenetically mark the location of the centromere on the chromosome. This work involves building centromeric chromatin from its component parts for analysis of its physical characteristics, developing biochemical assays to reconstitute steps in the process of establishing and maintaining the epigenetic mark, and using cell-based approaches to study the behavior of proteins involved in centromere inheritance and other essential aspects related to chromosome segregation at cell division.


Kathleen Boesze-Battaglia, Ph.D.

Degradative processes including phagocytosis and autophagy contribute to cell homeostasis with defects leading to disease


Professor, Department of Biochemistry, School of Dental Medicine; Professor of Biochemistry & Biophysics, Perelman School of Medicine
520 Leon Levy Building
Tel: 215-898-9167 / Fax: 215-898-3695
Dental School website

Autophagic processes play important physiological roles in development, ageing as well as the immune response, with it’s cyto-protective function compromised in numerous diseases. It is the major eukaryotic degradative process for cytosolic organelles, long–lived proteins as well as misfolded protein aggregates. Macro-autophagy hereafter referred to as autophagy is the primary mechanism by which cells “eat” myself, delivering sequestered cytosolic cargo to lysosomes for proteolytic degradation by lysosomal proteases . Our primary research goal is to understand the contribution of autophagy and phagocyte maturation in the progression of age related retinal degenerative disease and bacterial pathogenesis as it relates to periodontal disease. On a molecular level we investigate how intracellular components are sorted to decorate ingested materials for degradation using a combination of live cell confocal imaging techniques and classic biochemical/biophysical approaches. In a series of collaborative investigations we are involved in studies designed to understand the mechanism by which several bacterial toxins induce their cytotoxic affects.


Roberto Dominguez, Ph.D.

Actin cytoskeleton, structural biology

Professor of Physiology
728 Clinical Research Building
Tel: 215-573-4559 / Fax: 215-573-5851
Lab website

The actin cytoskeleton plays an essential role in multiple cellular functions, including cytokinesis, vesicular trafficking and the maintenance of cell shape and polarity. The driving force for these processes is the dynamic remodeling of the actin cytoskeleton into supramolecular functional networks. Remodeling of the cytoskeleton is a tightly regulated process, which involves hundreds of actin-binding and signaling proteins. The main focus of the research in our lab is to understand the molecular basis for how protein-protein interaction networks bring together cytoskeleton scaffolding, nucleation, elongation, and signaling proteins to accomplish specific cellular functions. Another area of significant interest is the study of large multi-domain proteins that connect the actin cytoskeleton to the cell membrane, and sense or induce membrane curvature.

Our primary research tool is protein X-ray crystallography. The atomic snapshots resulting from crystal structures provide a wealth of knowledge, but lack information about the dynamic aspects of protein-protein interaction. To obtain this kind of information we also use a host of other approaches, including mutagenesis, bio-informatics, and biophysical methods such as isothermal titration calorimetry (ITC), multi-angle light scattering (MALS), small and wide angle X-ray scattering (SAXS/WAXS). The lab collaborates with cell biologists and electron microscopists to study actin cytoskeletal proteins in the cellular environment.


Roland L. Dunbrack, Jr. Ph.D.

Methods and applications of protein structure prediction

Adjunct Professor of Biochemistry & Biophysics
Member, Institute for Cancer Research, Fox Chase Cancer Center
Tel: 215-728-2434 / Fax: 215-728-2412
Fox Chase Cancer Center website

The Dunbrack group concentrates on research in computational structural biology, including homology modeling, fold recognition, molecular dynamics simulations, statistical analysis of the PDB, and bioinformatics. In developing these methods, we use methods from various areas of mathematics and computer science, including Bayesian statistics and computational geometry. We place an emphasis on large-scale benchmarking of new methods and comparison with existing methods. We are interested in applying comparative modeling to important problems in various areas of biology. Areas of particular interest include DNA repair, proteases and other peptide-binding protein families, and membrane proteins.


P. Leslie Dutton, Ph.D.

Oxido-reductase engineering; design and chemical synthesis of redox proteins

Professor of Biochemistry & Biophysics
1005 Stellar-Chance Labs
Tel: 215-898-0991 / Fax: 215-573-2235
Departmental website / Lab website

The Dutton lab is interested in determining factors governing electron tunneling through natural proteins engaged in electron transfer, energy conversion, signaling, regulation and enzyme redox catalysis. We are also involved in de novo design and synthesis of proteins engineered to perform natural functions such as electron transfer, proton translocation, charge driven conformational changes and redox catalysis in structured highly simplified settings.


S. Walter Englander, Ph.D.

Protein folding; structure, structure change, and dynamics; H-exchange; NMR

Professor of Biochemistry & Biophysics
1006-8 Stellar-Chance Labs
Tel: 215-898-4509 / Fax: 215-898-2415
Departmental website / Lab webpsite

Dr. Englander's laboratory is interested in macromolecular structure, dynamics, and function and has developed the use of hydrogen exchange (HX) approaches in protein and nucleic acid studies.  Many hydrogens in proteins and nucleic acids are in continual exchange with the hydrogens in solvent water. These can provide literally hundreds of probe points that are sensitive to structure, structure change, internal dynamics, energy, and functional interactions at identifiable positions throughout a macromolecule. Work in this lab has explained the chemistry of protein and nucleic acid HX processes and has formulated the physical models that appear to explain the ways in which internal motions in proteins and nucleic acids determine the HX rates of their individual protons. The lab has developed and is using special hydrogen exchange methods that can measure the specific parts of any protein involved in any function, the protein folding process as it occurs on a sub-second time scale, the energetic stability of individual bonding interactions, structure change, etc.


Hua-Ying Fan, Ph.D.

Regulation of chromatin structure and its impact on human diseases

Assistant Professor of Biochemistry & Biophysics, and Genetics
9-133 Smilow Center for Translational Research
Tel: 215 573-5705
Departmental website

The Fan lab is interested in understanding the mechanisms of epigenetic regulation. Epigenetics describes the process by which a specific transcriptional program, induced by a signal, is maintained and inherited through cell divisions without the necessary presence of the original signal. Chromatin structure holds the secrets of epigenetic regulation. To dissect the mechanisms of epigenetic regulation, our research is focused in two main directions. First, we study how ATP-dependent chromatin remodelers regulate chromatin structure and how defects in these activities can lead to disease. Currently, we are using CSB (Cockayne Syndrome complementation group B) as a model protein to understand the function of ATP-dependent chromatin remodeling in DNA repair, aging and cancer. Second, we wish to understand how epigenetic regulatory mechanisms influence cancer cell self-renewal and differentiation, mechanisms that might impact the programming and reprogramming capacity of cancer cells. Results from our studies will, therefore, not only shed light on fundamental mechanism of epigenetic regulation, but will provide novel insights into the causes and mechanisms of disease.


Kathryn M. Ferguson, Ph.D.

Structural biology, growth factor receptor signaling, molecular mechanisms of protein-protein interactions

Associate Professor of Physiology
364 Clinical Research Building
Tel: 215-573-1207 (office) / 215-746-2816 (lab)

We are interested in understanding molecular mechanisms that regulate receptor signaling at and across membranes. We continue our long-standing interest in the regulation of the Epidermal Growth Factor Receptor (EGFR) family of receptor tyrosine kinases (RTKs), and also expand our study to several other families of RTKs. Rekindling an early interest in pleckstrin homology domains, we are also investigating the role of lipid binding modules in several settings. To address these questions we use a combination of biophysical, structural, biochemical and cellular approaches.


Feng Gai, Ph.D.

Spectroscopic study of protein folding/misfolding

Professor of Chemistry
254 Chemistry Building
Tel: 215-573-6256 / Fax: 215-573-2112
Lab website

The focus of our research is to study how proteins fold from random or quasi-random coils to their biologically functional conformations. We are particularly interested in the kinetic aspects of the folding mechanisms. Novel laser spectroscopic methods are being used and developed to study the early folding events and folding intermediates. Recent works involve the study of the helix-coil transition, helix-helix interaction, and x-sheet formation. In addition, single molecule techniques, such as confocal fluorescence spectroscopy and microscopy, are being used to investigate the heterogeneity in folding kinetics as well as protein spontaneous fluctuation and polymerization.


Yale E. Goldman, M.D., Ph.D.

Molecular motors and protein synthesis studied by single molecule biophysics

Professor of Physiology, and Biochemistry & Biophysics
615B Clinical Research Building
Tel: 215-898-4017 / Fax: 215-898-2653
Pennsylvania Muscle Institute website

Molecular motors are energy transducing nano-machines that power many cell biological motions such as targeted vesicle transport and cell division. Their mechanisms can be probed by biophysical, physiological, chemical and structural methods. We are developing novel techniques, such as nanometer tracking and polarization of single molecule fluorescence and infrared optical traps (laser tweezers), to map protein structural changes in real time and to relate them to the enzymology and mechanics of their mechanisms.

The ribosome translates the genetic code into amino acid sequences with enormous fidelity and also constitutes a motor translocating along the mRNA exactly 3 bases per step. Energy from splitting GTP by G-protein elongation factors (EFs) is transformed into translational accuracy and maintenance of the reading frame. Powerful techniques developed for studies on motor proteins, including single molecule fluorescence resonance energy transfer and high speed optical traps, are being applied to understand the structural biology, energetics and function of EFs and their interaction with the ribosome.



Harry Ischiropoulos, Ph.D.

Biological chemistry of nitric oxide; oxidative processes, protein aggregation and neurodegeneration.

Gisela and Dennis Alter Research Professor of Pediatrics, and Pharmacology
417 Abramson Research Center
Tel: 215-590-5320
Lab website

The research efforts of my laboratory are focused on three areas:
1) Biological chemistry of nitric oxide in cardiovascular diseases and thrombosis. We employ proteomics to discover the complement of proteins modified post-transitionally by nitric oxide on cysteine and tyrosine residues.The functional consequences of these modifications on nitric oxide signaling in atherosclerosis and deep vein thrombosis are under investigation.
2) Oxidative processes in protein aggregation and neurodegeneration. We use cellular and mouse models to investigate the role of oxidative chemistry in the aggregation of α-synuclein and in neurodegeneration.
3) Functional proteomics to turn inventories of cellular secretomes to biological insights by defining secreted proteins that regulate neuron growth, differentiation and death


Virginia M.-Y. Lee, Ph.D.

Pathobiology of Alzheimer's and Parkinson's disease

Professor of Pathology & Laboratory Medicine
Director, Center for Neurodegenerative Disease Research
The John H. Ware 3rd Professor in Alzheimer’s Research
3 Maloney, Hospital of the University of Pennsylvania
Tel: 215-662-6427 / Fax: 215-349-5909
CNDR website

Dr. Virginia M.-Y. Lee’s research interest focuses on tau, a-synuclein and amyloid beta precursor protein (APP), and their roles in the pathobiology of neurodegenerative diseases such as Alzheimer's disease (AD), Parkinson’s disease (PD), and frontotemporal dementias (FTD). In particular, we wish to determine the pathogenesis of senile plaques, Lewy bodies and neurofibrillary tangles because these are major lesions found in the brains of AD patients and other neurodegenerative diseases. Information obtained from research program may shed light on how neurons degenerate in AD and PD and lead to a better understanding of the etiology of these diseases. A multi-disciplinary approach (including biochemical and molecular studies of neuronal culture systems, animal models and human tissues obtained at autopsy) is used in the laboratory to address these research issues in common with these neurodegenerative diseases. Our other research efforts focus on an increased understanding of the normal functions of tau, synucleins, and APP.


Mark A. Lemmon, Ph.D.

Biochemistry/biophysics of intermolecular interactions of growth factor receptor signaling

George W. Raiziss Professor of Biochemistry & Biophysics
322A Clinical Research Building
Tel: 215-898-3072 / Fax: 215-573-4764
Departmental website / Lab website

Research interests of the Lemmon lab:
Signaling by receptor tyrosine kinases from the ErbB/HER family
EGF receptor signaling in Drosophila
Membrane recruitment by phosphoinositide-binding domains
Dynamin-family large GTPases in intracellular trafficking


Mitchell Lewis, D.Phil.

Gene regulation; protein crystallography; structural basis of recognition

John Morgan Professor of BIomedical Research and Education
Department of Biochemistry & Biophysics
813B Stellar-Chance Labs
Tel.: 215-898-0711 (lab) 215-898-0949 (office) / Fax: 215-898-4217
Departmental website

The major objective of our research is to understand how proteins respond to metabolites and regulate transcription. Our work has focused on the repressor of bacteriophage lambda and the lac operon of E. coli. For almost half a century, these two systems have served as the paradigm for understanding gene regulation. The primary focus of our lab has been to provide detailed structural information on these two systems.


Paul A. Liebman, M.D.

G-protein-receptor-arrestin mechanisms; visual signal transduction

Professor of Biochemistry & Biophysics
260 Anatomy-Chemistry Building
Tel.: 215-898-6917 / Fax: 215-573-8093
Departmental webpsite

Research Interests of the Liebman Lab:

  • Analysis of misfolding of signaling proteins upon loss of their obligatory small ligand. Role of misfolding in biological aging
  • Thermodynamics, kinetics and protein-protein contact mechanism of signal transduction proteins.
  • Computational modeling, complex systems analysis of simultaneous actions of GTPase activator protein, phosducin, arrestin and receptor phosphorylation in signal transduction.
  • Rich interplay of analytical math, biophysical instrumentation, reaction chemistry and physics, molecular graphics computing, dual wavelength kinetic spectroscopy, intrinsic tryptophan and tyrosine fluorescence dynamic and static light scattering, centrifugal and gel filtration polymer size analysis, microcalorimetry, CD, osmotic stress, hydrostatic pressure plus all the standard wet lab preparation techniques.


Ronen Marmorstein, Ph.D.

X-ray crystallography, chromatin regulation, tumor suppressors, oncoproteins, kinases, aging, structure-based inhibitor design

Professor of Biochemistry & Biophysics
454 Biomedical Research Building II/III
Tel: 215-898-7740; Fax: 215-746-5511
Departmental website

The laboratory uses a broad range of molecular, biochemical and biophysical research tools centered on X-ray crystal structure determination to understand the mechanism of macromolecular recognition and post-translational histone and protein modifications in the regulation of gene expression, chromatin and epigenetics. The laboratory is particularly interested in gene regulatory proteins and 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 develop protein-specific small-molecule compounds to treat such diseases.


Hillary C.M. Nelson, Ph.D.

Structural biology; transcription; protein-DNA interactions; heat shock response

Associate Professor of Biochemistry & Biophysics
813A Stellar-Chance Labs
Tel: 215-573-7473
Nelson Department webpage


E. Michael Ostap, Ph.D.

Biochemistry of contractile proteins, biophysics of cell motility, and characterization of unconventional myosins

Professor of Physiology
Director, Pennsylvania Muscle Institute
700A Clinical Research Building
Tel: 215-573-9758 (office); 215-898-3685 (lab)
Lab website

The goal of our research is to understand the function, regulation, and molecular mechanism of the ubiquitously expressed molecular motors called myosins. The physiological roles and molecular mechanisms of many members of the myosin superfamily are not well understood. To better define the roles of myosin isoforms, we are using a rigorous interdisciplinary approach that combines chemistry, biophysics, cell, and molecular biology. We are obtaining a physical framework in which to discuss the cellular functions of myosins by investigating the enzymatic and structural properties of native and recombinant myosin isoforms, and we are investigating the in vivo localization, organization, dynamics, and physiology of myosin-I in fixed and live cells using high-resolution microscopy techniques.



Amish Patel, Ph.D.

Predictive computational framework for characterizing biomolecular hydration, interactions and assemblies

Reliance Industries Term Assistant Professor
Department of Chemical and Biomolecular Engineering
311A Towne Building
Tel: 215-898-9682
Lab website

The last two decades have seen an incredible revolution in structural biology: over 90,000 protein structures have now been solved at atomic resolution. Translating this wealth of static structural information into a molecular understanding of dynamic intracellular processes represents a grand challenge in molecular biology, with grave implications on our understanding of human health and disease. Progress in this area hinges on our ability to understand, predict, and manipulate the interactions of various proteins, given their precise structure, i.e., out of the veritable menagerie of molecules that a protein encounters in the cellular milieu -- ligands, peptide fragments, nucleic acids, membranes, and other proteins -- which molecules will it interact favorably with, how strong will the interaction be, and what are the strategies for modulating the interaction strength?
Based on recent work in our group and those of others, we hypothesize that the biggest challenge in accurately predicting protein interactions is precisely accounting for the role of water in mediating these interactions. Because all of biology happens in water, every biomolecular binding process requires the dehydration of the binding partners, with direct interactions between them replacing their individual interactions with water. While the direct interactions are straightforward to estimate, the protein-water interactions are difficult to quantify because proteins have incredibly complex surfaces that disrupt the inherent structure of water (strong hydrogen bonds) in countless different ways. So, what makes predicting protein interactions particularly challenging, is quantifying this disruption of the hydration shell water structure, which depends not only on the chemistry of the underlying protein surface, but also on the precise topography and chemical pattern of amino acids. Using principles of liquid state theory in conjunction with novel simulation techniques, we are working towards developing a framework, which will transform our ability to accurately and efficiently predict protein interactions, and provide a basis for understanding how proteins respond to various perturbations, aggregate into multi-meric assemblies, and are able to function.



Trevor M. Penning, Ph.D.

Structure-function of aldo-keto reductases; role in steroid hormone action and chemical carcinogenesis

Professor of Pharmacology, and Biochemistry & Biophysics
Director, Center of Excellence in Environmental Toxicology (CEET)
1315 Biomedical Research Building II/III
Tel: 215-898-9445
Fax: 215-573-0200
Departmental website/ AKR webpage / CEET website

The aldo-keto reductase (AKR) superfamily: roles in steroid hormone action and mechanisms of carcinogen activation. Structure-function studies are being performed on discrete AKR isoforms that regulate the occupancy and trans-activation of steroid hormone receptors. The goal is rational drug-design. Some AKRs are implicated in the metabolic activation of polycyclic aromatic hydrocarbons which are human carcinogens by forming reactive and redox-active o-quinones. The DNA-damaging events that result from quinone formation and the mutational consequences of these lesions are being studied.


E. James Petersson, Ph.D.

Semi-synthesis of labeled proteins to probe and control conformation


Assistant Professor of Chemistry
350N Chemistry Building
Tel: 215-898-0487
Petersson lab webpage

Protein motion underlies both proper function and disease in biological systems. Many signaling and transport proteins require complex rearrangements for function, and some proteins, such as amyloids, misfold into toxic conformations. Studying these protein motions not only aids our understanding of diverse biological phenomena, it also contributes to an important fundamental problem in biochemistry: understanding how motions propagate from one end of a protein to another. The Petersson laboratory is developing tools to address questions of how dynamic proteins mediate communication and how the cellular environment catalyzes protein misfolding, from detailed in vitro folding studies to modeling protein motion in living cells. These tools include novel chromophores, which we synthesize and incorporate into proteins through unnatural amino acid mutagenesis and synthetic protein ligation.


Ravi Radhakrishnan, Ph.D.

Computational structural biology and systems biology; cell membrane mediated trafficking; targeted drug delivery; cancer signaling


Professor of Bioengineering, and Biochemistry & Biophysics
540 Skirkanich Hall
Tel: 215-898-0487 / Fax: 215-573-2071
Lab website

Radhakrishnan directs a computational research laboratory with research interests at the interface of chemical physics and molecular biology. The goal of the computational molecular systems biology laboratory is to provide atomic and molecular level characterization of complex biomolecular systems and formulate quantitatively accurate microscopic models for predicting the interactions of various therapeutic agents with innate biochemical signaling mechanisms. The lab specializes in several computational algorithms ranging from techniques to treat electronic structure, molecular dynamics, Monte Carlo simulations, stochastic kinetic equations, and complex systems analyses in conjunction with the theoretical formalisms of statistical and quantum mechanics, and high performance computing in massively parallel architectures.


Heinrich Roder, Ph.D.

NMR; protein folding mechanism; protein structure, dynamics and function

Adjunct Professor of Biochemistry & Biophysics
Senior Member, Institute for Cancer Research
Fox Chase Cancer Center,
Tel: (215) 728-3123 / Fax: (215) 728-3574
Lab website

To decipher the mechanism by which proteins acquire their precisely folded three dimensional structures remains one of the most important challenges of structural biology. We approach this complex problem by using optical and NMR methods for detailed structural, thermodynamic and kinetic studies on several small proteins with diverse structural characteristics. To monitor their folding or unfolding reactions, we rely on various optical probes coupled with rapid mixing techniques, including a new continuous-flow method with greatly improved time resolution (~50 microsec). Hydrogen exchange and NMR methods provide insight into the structural and dynamic properties of kinetic intermediates and partially folded equilibrium states. By combining these biophysical approaches with site-specific mutagenesis, we can elucidate the role of individual residues in stabilizing the various conformational states that participate in folding.


Harvey Rubin, M.D., Ph.D.

Pathogenesis of dormancy in mycobacterium tuberculosis; biomolecular computation and enzymology and cell biology of serine proteases and serine protease inhibitors

Professor of Medicine
522 Johnson Pavilion
Tel: 215-662-6475 / Fax: 215-662-7842
ISTAR website

The work in the lab is focused in three areas: elucidating the genetic and metabolic regulatory networks that allow tuberculosis to persist in the human host for years, determination of the molecular basis of serine protease inhibition and mathematical modeling of complex biomolecular systems.


Jeffery G. Saven, Ph.D.

Theory, simulation and design of proteins and folding molecules

Professor of Chemistry
266 Cret Wing of Chemistry
Tel: 215-573-6062 / Fax: 215-573-2112
Lab website

The Saven group uses primarily theory and computation to study biomolecules, polymers, and condensed phase systems. 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, design of nonbiological folding molecules, and developing "physically-based" search methods for sequence databases.


Kim A. Sharp, Ph.D.
Graduate Group Chair  

Theory of protein and nucleic acid structure and function

Associate Professor of Biochemistry & Biophysics
805A Stellar-Chance Labs
Tel.: 215-573-3506 / Fax: 215-898-4217
Departmental website / Lab website

The goal of the research is to gain a detailed understanding at the molecular and physical chemical level of how proteins bind and recognize other proteins, drugs, ligands and nucleic acids. Theoretical and computational methods used include Poisson-Boltzmann electrostatics, Molecular and Browian Dynamics, and Monte Carlo simulations.


James Shorter, Ph.D.

Regulation of beneficial or neuropathogenic prions and amyloids by protein-remodeling factors, molecular chaperones, and small molecules

Associate Professor of Biochemistry & Biophysics
805B Stellar-Chance Labs
Tel: 215-573-4256 (office) / 215-573-4257 (lab)
Lab website /Departmental website
Read about Dr. Shorter's NIH Director's New Innovator Award (October 2007)

Life demands that proteins fold into elaborate structures to perform the overwhelming majority of biological functions. We investigate how cells achieve such successful protein folding. In particular, we seek to understand how cells prevent, reverse, or even promote the formation of prion and amyloid fibers.


Emmanuel Skordalakes, Ph.D.

X-ray crystallography; telomere biology; cancer and aging

Wistar Institute Associate Professor of Biochemistry & Biophysics
321 Wistar Institute
Tel: 215-495-6884 (Office); 215-898-2202 (Lab)
Lab website

In recent years several links have begun to emerge between the integrity of eukaryotic chromosome ends, known as telomeres, and both cancer and aging. Studies from several research laboratories have identified proteins involved in replicating and regulating telomere length and stability; however, the function of these telomere maintenance factors and their role in human disease are far from fully established. The long-term goal of the Skordalakes laboratory is to understand how telomeric complexes protect chromosome ends and mediate their replication and apply this information in pursuit of anticancer therapies.


David Speicher, Ph.D. 

Cancer proteomics; structure-function of membrane associated proteins: protein chemistry and mass spectrometry

Wistar Institute Professor of Biochemistry & Biophysics
Caspar Wistar Professor in Computational and Systems Biology
Director, Center for Systems and Computational Biology, Wistar Institute
151 Wistar Institute
Tel: 215-898-3972
Fax: 215-898-0664
Lab website

Our research group primarily focuses on proteomics of human diseases and structure-function of protein-protein interactions. We are currently pursuing two structure-function projects that primarily utilize biophysical methods, such as isothermal titration calorimetry and sedimentation equilibrium, and mass spectrometry to probe protein structures, protein-protein interactions and function. One project involves the giant membrane skeletal protein spectrin, a human actin crosslinking protein that plays a key role in stabilizing the plasma membrane in most cell types. Current studies focus on the proteotypical spectrin tetramers found in human red blood cells and their role in membrane purturbations caused by hereditary hemolytic anemia mutations. Another project involves structure-function analysis of peroxiredoxin 6, an antioxidant enzyme with glutathione peroxidase activity and phospholipase activity, which plays a critical role in protecting lung and other tissues from damage due to oxidative stress


Cecilia Tommos, Ph.D.

Protein radicals and electrochemistry; cation-x interactions; protein forced folding

Research Associate Professor of Biochemistry & Biophysics
905 Stellar-Chance Labs
Tel: 215-746-2444
Departmental website

Our work involves two different projects:
1) Understanding the redox chemistry of protein radicals. Amino-acid radicals represent key components in biological processes ranging from energy transduction to carcinogenesis and, yet, virtually nothing is known about the thermodynamic properties of these species. This situation reflects the simple fact that the characteristically reactive and thermodynamically hot radical state is highly challenging to study in the natural systems. We have created a model protein system specifically made to facilitate structural, spectroscopic and electrochemical studies of amino-acid radicals. Using this system we aim to systematically characterize the thermodynamic properties of amino-acid radicals as a function of structural motifs in the protein environment.
2) Developing a "protein forced folding" method for the structural analysis of intrinsically unfolded proteins. Structural genomics studies have revealed that a surprising large fraction of the proteins from various genomes, including that of humans, are unfolded under in vitro conditions. Several factors may contribute as to why a protein is found unfolded in the test tube, e.g., it lacks an essential ligand. Another possibility is that the test-tube protein lacks the unique environment of the densely packed cell in which molecular crowding stabilizes the compact folded state of the protein relative to its structurally more extended unfolded states. We showed in a pilot study that a highly unstable model protein could be forced folded into a well-defined structure by placing the protein in a reverse micelle "bag". When the size of the "bag" was made sufficiently small, the protein was observed to adopt the structurally more compact form of the folded protein. We are now in the process of exploring the potential of this confined-space approach to force fold naturally unfolded proteins. This project is conducted in collaboration with Professor Wand.


Gregory D. Van Duyne, Ph.D.

Structural biology; protein-protein interactions; x-ray crystallography

Jacob Gershon-Cohen Professor of Medical Science
Department of Biochemistry & Biophysics
809B Stellar-Chance Labs
Tel: 215-898-3058
Fax: 215-573-4764
Departmental website

We are interested in understanding on a structural and biochemical level how DNA and RNA molecules are maintained and processed by living cells. In addition to the mechanisms and regulation of genome replication and transcription, this includes processes such as DNA repair, site-specific and homologous recombination, transposition, condensation of chromosomes, chromosome pairing and segregation, and RNA trafficking and splicing. Our approach is to establish three-dimensional models of macromolecular assemblies relating to a particular biological question using X-ray diffraction methods and to then develop mechanistic and functional models that can be tested experimentally.


A. Joshua Wand, Ph.D.

Protein structure and dynamics; molecular recognition and signal transduction; NMR spectroscopy

Benjamin Rush Professor of Biochemistry & Biophysics
Office: 905 Stellar-Chance Labs
Main Laboratory: 902-904 Stellar-Chance Labs
NMR Laboratory: G6 Blockley Hall
Tel. 215-573-7288 (office); 215-573-7289 (main lab); 215-573-5969 (NMR lab) / Fax: 215-573-7290
Lab website
Departmental website

Dr. Wand's research focuses on exploring the relationships between static structure, structural dynamics and function in a range of protein systems. Current efforts are centered on calmodulin, a main player in calcium-mediated signal transduction, GP130, an somewhat promiscuous interleukin and antigen-antibody complexes. A key concept is the balance between changes in structure (enthalpy) and dynamics (entropy) in the setting of the free energy of association between proteins. They are also interested in similar issues in the context of interactions with small ligands such as drugs. Through these studies a remarkably rich manifold of fast dynamical modes have been revealed and a surprising functional role for them discovered.

The Wand lab is also committed to continuing improvement and development of novel NMR techniques. They have recently focused on high pressure NMR to probe the protein ensemble, sparse sampling methods for rapid and sensitivity-optimized data collection, NMR relaxation methods to measure conformational dynamics throughout the protein and a novel method to approach large soluble, unstable and membrane proteins by solution NMR methods. The latter approach involves the use of reverse micelle encapsulation to provide a protective environment for proteins to allow them to be dissolved in low viscosity fluids such as liquid ethane. The initial idea was to use the low viscosity of ethane to overcome the slow tumbling problem for solution NMR spectroscopy presented by large protein in water. Applications have since been expanded to studies of proteins of marginal stability by employing the confined space of the reverse micelle, suppression of protein aggregation to allow study of intermediates of aggregation such as occur in amyloid formation, and studies of both integral and peripherally anchored membrane proteins.


John W. Weisel, Ph.D.

Structural studies of molecular/cellular mechanisms in blood clotting and fibrinolysis

Professor of Cell & Developmental Biology
1054 Biomedical Research Building II/III
Tel.: 215-898-3573 / Fax: 215-898-9871
Departmental website

The research in this lab has focused on the molecular and cellular mechanisms of blood coagulation and fibrinolysis, as analyzed through the use of various biophysical and structural techniques, including visualization of molecules and supramolecular aggregates and measurements of mechanical properties of cellular and extracellular structures. Molecular mechanisms of the dissolution of the clot by the fibrinolytic system are under investigation. The interactions of integrins with various adhesive proteins and with the cytoskeleton is also a focus of research. The results of these studies have implications for basic mechanisms of protein-protein and protein-cell interactions as well as for clinical aspects of hemostasis, thrombosis and atherosclerosis.


Jeremy E. Wilusz, Ph.D.

Regulation of noncoding RNA biogenesis and function

Assistant Professor of Bichemistry & Biophysics
363 Clinical Research Building
Tel: 215-898-8862
Departmental website
Lab website

Most of the eukaryotic genome is transcribed, yielding a complex repertoire of RNAs that includes tens of thousands of noncoding RNAs with little or no predicted protein-coding capacity. Among these are well-studied small RNAs, such as microRNAs, as well as many other classes of small and long transcripts whose functions and mechanisms of biogenesis are less clear – but likely no less important. Our goal is to characterize the mechanisms by which these poorly characterized noncoding RNAs are generated, regulated, and function, thereby revealing novel insights into RNA biology and developing new methods to treat diseases. Our current efforts are two-fold. First, we are continuing to characterize the MALAT1 locus, which is over-expressed in many human cancers and produces a long nuclear-retained noncoding RNA. Despite being an RNA polymerase II transcript, the 3’ end of MALAT1 is produced by recognition and cleavage of a tRNA-like structure by RNase P. Mature MALAT1 thus lacks a poly(A) tail, yet is protected from 3’-5’ exonucleases by a highly conserved triple helical structure. Second, we are studying the mechanism by which circular RNAs are produced and function. These circular transcripts are generated from protein-coding genes via an unusual pre-mRNA splicing reaction, yet it is largely unclear why the splicing machinery selects certain regions of the genome (and not others) to circularize.