Biochemistry and Molecular Biophysics Graduate Group

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pixelBioenergetics, Metabolism, and Membrane

Joseph A. Baur, Ph.D.

Molecular mechanisms of aging and caloric restriction

Assistant Professor of Physiology
12-114 Smilow Center for Translational Research
Tel: 215-746-4585 / Fax: 215-898-5408
Email: baur@mail.med.upenn.edu

The Baur lab is interested in the basic mechanisms that lead to aging. Age is the most important risk factor for many of the diseases affecting Western society today, including cancer, cardiovascular disease, and neurodegenerative disorders.

 

Paul H. Axelsen, M.D.

Biophysical studies of molecular recognition and rational drug design

Professor of Pharmacology, Biochemistry & Biophysics, and Medicine
105 Johnson Pavilion
Tel: (215) 898-9238
Email: axe@upenn.edu
Axelsen Lab Page

Research Themes - Infectious disease (antibiotics, antimicrobial peptides, antibiotic resistance, vancomycin); Neurodegeneration (amyloidogenesis, Alzheimer's disease); Cardiovascular disease (lipoprotein structure and function)
Focus Areas - Rational drug design and molecular recognition; Protein-lipid interactions (involved in protein folding, misfolding, and amyloidogenesis); Mechanisms and consequences of oxidative lipid membrane damage

 

Fevzi Daldal, Ph.D.

Genetics, structure-function, regulation and biogenesis of cytochromes

Professor of Biology, and Biochemistry & Biophysics
103B Carolyn Lynch Laboratory
Tel: 215-898-4394; Lab: 215-898-8394 / Fax: 215-898-8780
Email: fdaldal@sas.upenn.edu
Daldal homepage

Our work is focused on the structure, function, assembly, biogenesis and regulation in response to environmental signals (light and oxygen) of multi-subunit, prosthetic groups bearing membrane proteins involved in cellular energy transduction (photosynthesis and respiration) pathways. These proteins are vital for important cellular functions that extend from ATP synthesis to secretion, solute transport, motility and thermogenesis. Their dysfunction severely compromises cellular energy production, and leads to neurological and muscular diseases in humans, or to lower crop yields in plants. We employ molecular genetic and genomic/proteomic approaches in combination with molecular biological, biochemical, biophysical and structural techniques, and we work with the purple non-sulfur facultative photosynthetic bacterium Rhodobacter capsulatus as a model organism instead of eukaryotic organelles that are more refractory to multidisciplinary analyses. Ongoing research involves the cytochrome bc1 complex, the cytochrome cbb3 oxidase and their physiological electron carriers.

 

Bohdana M. Discher, Ph.D.

Design and assembly of proteins for transmembrane electron transfer

Research Assistant Professor of Biochemistry & Biophysics
901C Stellar-Chance Labs
Tel: 215-898-5668 Fax: 215-898-0465
Email:bohdana@mail.med.upenn.edu
Discher Home Page

The Discher lab is using a synthetic biology approach to build minimal protein constructs (referred to as maquettes) for energy transduction. We focus our efforts on the design of amphiphilic maquettes spanning natural and synthetic membranes and on positioning of variety of cofactors within these maquettes to form transmembrane electron transport chains. We are applying our maquettes to study light-activated and redox driven catalysis, proton coupled electron transfer (PCET), and reactive oxygen species (ROS) generation.

 

P. Leslie Dutton, Ph.D.

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

Eldridge Reeves Johnson Professor of Biochemistry & Biophysics
1005 Stellar-Chance Labs
Tel: 215-898-0991 / Fax: 215-573-2235
Email: dutton@mail.med.upenn.edu
Dutton Departmental Page / Dutton Lab

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
Email: engl@mail.med.upenn.edu
Englander Departmental Page / Englander Lab

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.

Methods in use include the range of protein biophysical techniques including 2D NMR, mass spectrometry, fast reaction stopped-flow, spectroscopy, and mutational analysis. The lab has in recent years produced a coherent explanation for how proteins fold, and discovered the new foldon dimension of protein structure and behavior. Present work is directed at testing and enlarging the folding model and investigating the broader significant of the foldon paradigm.

 

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

Motor proteins studied by photochemistry and spectroscopy

Professor of Physiology, and Biochemistry & Biophysics
611B Clinical Research Building
Tel: 215-898-4017 / Fax: 215-898-2653
Email: goldmany@mail.med.upenn.edu
Pennsylvania Muscle Institute

Actomyosin in muscle is an energy transducer that can be probed by biophysical, physiological, chemical and structural methods. Modified forms power many cell biological motions such as targeted vesicle transport and cell division. We are developing novel techniques, such as single molecule fluorescence polarization and laser photolysis of 'caged molecules', to map protein structural changes in real time and to relate them to the enzymology and mechanics of the mechanism.

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 and optical traps, are being applied to understand the structural biology, energetics and function of EFs and their interaction with the ribosome.

 

Roland G. Kallen, M.D., Ph.D.

Structure, function, and regulation of expression of ion channel

Professor of Biochemistry & Biophysics
913B Stellar-Chance Building
Tel: 215-898-5184, 898-8348 / Fax: 215-573-7058
Email: rgk@mail.med.upenn.edu
Kallen Departmental Page

The action potential responsible for muscle contraction involves the voltage-gated sodium channel. We are studying the conformations of parts of the molecule in the activated, inactivated, closed states, determining the architecture of sites of drug and toxin binding for rational drug design, and elucidating the regulation of the expression of these proteins during development and in disease states.

 

Zhe Lu, M.D., Ph.D.

Structure-function relationship of ion channels; molecular mechanisms of protein-protein interactions

Professor of Physiology
728 Clinical Research Building
Tel.: 215-573-7711 / Fax: 215-573-1940
Email: zhelu@mail.med.upenn.edu
Lu Physiology website

Dr. Lu's laboratory investigates the molecular and the biophysical mechanisms of inward-rectifier potassium channels and cyclic-nucleotide-gated channels, using a combined approach of biophysics, biochemistry and molecular biology. Specifically, they investigate the channel mechanisms that enable the inward-rectifier potassium channels to control cardiac pacemaker rate, to regulate communication strength between neurons and to couple blood glucose level to insulin secretion, and the mechanisms that enable the cGMP-gated channel to mediate visual photo-transduction in the eye. Additionally, they develop specific inhibitors for various types of physiological and pathophysiological important ion channels through both passive screening and active design.

 

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)
Email: ostap@mail.med.upenn.edu
Ostap Laboratory Page

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.

 

Trevor M. Penning, Ph.D.

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

Professor of Pharmacology, Biochemistry & Biophysics, and Obstetrics & Gynecology
Director of Center of Excellence in Environmental Toxicology (CEET)
130C John Morgan Building
Tel: 215-898-9445/1186
Fax: 215-573-2236
Email: penning@mail.med.upenn.edu
Penning Pharmacology website / AKR website / 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.

 

Ravi Radhakrishnan, Ph.D.

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

 

Associate Professor of Bioengineering, and Biochemistry & Biophysics
540 Skirkanich Hall
210 S. 33rd Street
Tel: 215-898-0487 / Fax:215-573-2071
Email: rradhak@seas.upenn.edu

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.

 

Brian M. Salzberg, Ph.D.

Multiple-site optical recording; excitation-secretion coupling; neural networks

Professor  of Neuroscience, and Physiology
234 Stemmler Hall
Tel: 215-898-2441
Fax: 215-573-2015
Email: bmsalzbe@mail.med.upenn.edu
Salzberg Neuroscience Web page

Certain substances, when bound to the membranes of neurons, cardiac and skeletal muscle, salivary acini, and other cells, behave as molecular indicators of membrane potential. The optical properties of these molecules, most notably fluorescence and absorbance, vary in a linear fashion with potential and may, therefore, be used to monitor action potentials, synaptic potentials, or other changes in membrane voltage from a large number of sites at once, without the necessity of using electrodes. Our laboratory is engaged in the development of more sensitive probes, extending the technology associated with their use, and in using these molecular voltmeters for optical recording of membrane potential from hitherto inaccessible regions of single neurons such as axon and neuroendocrine terminals and axonal and dendritic processes, and from many sites simultaneously in small assemblages of neurons and electrical syncitia, in order to study the spatial and temporal patterning of activity. Also, we are using dynamic high bandwidth atomic force microscopy to monitor extremely rapid mechanical events in nerve terminals and elsewhere in order better to understand neurosecretion.

 

Kim A. Sharp, Ph.D. 
Interim 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
Email: sharpk@mail.med.upenn.edu
Sharp Departmental Page / Sharp Lab Page

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.

 

David W. Speicher, Ph.D.

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

Wistar Institute Professor of Biochemistry & Biophysics
151 Wistar Institute
Tel: 215-898-3972
Fax: 215-898-0664
Email: speicher@wistar.org

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

 

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
Email: wand@mail.med.upenn.edu
Wand Departmental Page

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.

 

Kathryn E. Wellen, Ph.D.

Cancer cell metabolism, nutrient sensing

 

Assistant Professor of Cancer Biology
611 Biomedical Research Building II/III
Tel: 215-746-8599 / Fax: 215-573-6725
Email: wellenkf@exchange.upenn.edu
Wellen Departmental Page

Our laboratory is interested in understanding how nutrient metabolism interfaces with signaling and transcriptional networks, with a current focus on metabolic regulation of the epigenome. Diseases such as cancer and diabetes are characterized by significant epigenetic and cell metabolic alterations. Chromatin modifications such as histone acetylation are sensitive to changes in nutrient metabolism, although the contribution of metabolism to epigenetic regulation in normal physiology or in disease states is not known. Current goals of our research include defining the molecular mechanisms that link cellular metabolism to the epigenome and investigating the functional significance of this interaction in cancer and metabolic diseases.

 

David F. Wilson, Ph.D.

Integration of metabolism; oxidative phosphorylation; neuroregulation

Professor of Biochemistry & Biophysics
901A Stellar-Chance Labs
Tel: 215-898-6382 / Fax: 215-573-3787
Email: wilsondf@mail.med.upenn.edu
Wilson Departmental Page

My research is on the regulation of cellular and tissue metabolism in vivo, with particular focus on the role of oxygen in tissue energy metabolism. This program covers several different tissues, including brain, liver, heart, and eye, and involves several models of ischemia/hypoxia and reoxygenation.  We have developed an optical method for noninvasive measurement of oxygen, based on oxygen dependent quenching of phosphorescence, and are utilizing this technology for quantitative determine the oxygen dependence of tissue metabolism and function.