William A. Bernhard, Ph.D.
We live in an invisible sea of ionizing radiation, consisting of x-rays, g-rays and cosmic rays. Our radiation exposure is increased by its use in medicine and industry. The benefits of these applications must be weighed against the risk of radiation inducing cancer or leukemia. Central to this risk assessment is understanding the mechanisms by which radiation damages DNA. Our group studies these mechanisms using a variety of biophysical techniques, including electron paramagnetic resonance, electron nuclear double resonance, mass spectrometry, and chromatography.

Kara L. Bren, Ph.D.
Metalloproteins utilize a limited set of metal cofactors to perform a diverse array of functions such as electron transfer, ligand binding, and stereospecific oxidation of substrates. The polypeptide matrix that surrounds metal cofactors in metalloproteins is responsible for tuning the function of the metal site. The metal ion, in turn, influences the stability and folding of the polypeptide matrix. We are interested in gaining a more complete understanding of how the protein environment controls reactivity of metal ions, and how the properties of metal ions influence metalloprotein stability and folding.

Mark E. Dumont, Ph.D.
G protein-coupled receptors mediate cellular responses to a variety of sensory stimuli, hormones, growth factors, and neurotransmitters. We are interested in understanding  the molecular mechanism by which the extracellular signal is transduced  to G proteins in the cytoplasm, via seven-transmembrane  receptors.  We are using yeast genetics to study the regulation of signaling and the functional and structural properties of fungal and  mammalian receptor mutants.

Thomas Foster, Ph.D.
Photodynamic therapy (PDT) is a photochemical strategy to treat localized cancers and other diseases. It has recently received limited approval in the U.S. and several other countries. Our laboratory investigates various biophysical aspects of this interesting therapy and related problems in biomedical optics. Among these, we are interested in optical properties of tissue and in spectroscopic and imaging methods to characterize tumor oxygenation and other aspects of the tumor micro-environment, including enzyme activity, host responses and gene induction.

Alan Grossfield, Ph.D.
The biophysics of membranes and membrane proteins is critical to understanding the molecular-level mechanisms of a host of biological processes, including signaling, homeostasis, and some forms of immune response. My laboratory is focused on investigating these phenomena using computational techniques, primarily molecular simulation. Presently, we are using molecular dynamics simulations to characterize the membrane-lysing mechanism of antimicrobial lipopeptides, a new class of antibacterial drugs which selectively target bacteria based on differences in lipid headgroup composition. We are also interested in examining GPCR structure and function, peptide-protein interactions, and in developing new methods to represent the membrane environment implicitly and interpret two-dimensional wide angle X-ray scattering experiments on lipid bilayers.

Thomas E. Gunter, Ph.D.
Calcium is a second messenger that activates many enzymes in the cell. We are interested in the physiological properties of calcuim ion transport in the mitochondria and the role of calcium in the regulation of ATP production. Manganese is a toxin believed to use similar ion channels as calcium. Because Manganese is an additive in gasoline fuel, we are investigating the organelles, ion transport properties, target proteins and toxicity of manganese.

Jeffrey J. Hayes, Ph.D.
During the cell cycle, genomic DNA assembles into a compact, higher ordered chromatin fiber. The organization  of chromatin structure  is regulated in a gene-specific fashion and integrated with the machinery that controls transcription.  Our laboratory studies defined protein-DNA interactions, protein modification and mutations that  influence chromatin structure and gene regulation. Specific mutations of histone proteins are being used to probe  protein domains involved in site-specific contacts between DNA and nucleosomes.

Clara L. Kielkopf, Ph.D.
Inherited human diseases, including cancers and neuromuscular disorders, are frequently associated with defects in pre-mRNA splicing. In normal cells, pre-mRNA splicing enables single genes to encode multiple protein variants. We use biophysical methods to investigate the mechanisms of normal pre-mRNA splice site recognition, and to identify possible sources of pre-mRNA splice site defects in human genetic diseases.

Michael R. King, Ph.D.
The adhesion of cells with surfaces in the microvasculature is important in the inflammatory response, lymphocyte homing to lymphatic tissues, and stem cell homing. We use a combined approach of in vitro flow chamber experiments and state-of-the-art numerical simulations to examine the effect that flow disturbances in the human vasculature affect the dynamics of blood cell adhesion to surfaces. By focusing on the interplay between fluid mechanics, specific chemical adhesion, and time-dependent levels of cell activation, we hope to elucidate the basic physical mechanisms of blood cell adhesion in inflammatory and cardiovascular disease.

Thomas R. Krugh, Ph.D.
We are interested in the three-dimensional structure of DNA and RNA oligomers, with an overall goal of relating structure to biological function. Two-dimensional NMR experiments are used to assign nucleic acid NMR resonances, and to measure intermolecular distances for energy minimization and molecular dynamics calculations used to determine three-dimensional structures.

Lynne E. Maquat, Ph.D.
In numerous inherited diseases, frameshift and nonsense mutations result in mRNA degradation. Degradation provides a means to protect cells from the potentially deleterious effects of routine mistakes in gene expression and, remarkably, depends on proteins that bind mRNA as a consequence of pre-mRNA splicing. We are currently investigating the mechanistic links between nuclear splicing and cytoplasmic translation in order to gain insight into disease therapies.

David H. Mathews, M.D., Ph.D.
RNA plays many important cellular roles, including catalyzing peptide bond formation and phosphate bond rearrangements, protein localization, and post-transcriptional gene regulation. We are interested in the Computational Biology of RNA. We write and test new algorithms for structure prediction in order to better understand mechanisms and to improve pharmaceutical design.

James L. McGrath, Ph.D.
Our lab is examining the mechanisms of vascular endothelial cell (VEC) migration. Here we are combining mathematical modeling of motility and division, biochemical and genetic manipulation of cells, with time-lapse in vitro studies to arrive at an explanation of how VECs migrate as a collective.  We also work to understand the physical machinery of the actin-based cytoskeleton at the leading edge of motile cells. Here again we are developing a predictive engineering model that works hand-in-hand with an experimental system for measuring force production by reconstituted actin networks.

Benjamin L. Miller, Ph.D.
Nature has adopted an evolutionary strategy for the development of small-molecule ligands for proteins and nucleic acids. The focus of the Miller group is to utilize principles derived from Nature - combinatorial variation, self assembly, and molecular evolution - to derive small molecules capable of specific binding to selected protein, RNA, and DNA sequences. In this context, we use and develop methods for molecular design, combinatorial synthesis, multidimensional NMR spectroscopy, and traditional organic synthesis.

Lukas Novotny, Ph.D.
We use single molecule fluorescence detection to study the transport cycle of ion-exchange proteins (human AE1 and bacterial GlpT and OxlT). We synthesize double cys mutants and label them with fluorophores. Single-pair fluorescence resonance energy transfer allows us to measure the distances between the labeled sites and to monitor alterations in molecular structure that are critical to the catalytic cycle of these proteins, as well as the dynamics of these conformational changes. By studying a single protein at a time we avoid the problem of ensemble averaging and are able to reveal different conformational states.

Eric M. Phizicky, Ph.D.
Functional genomics is an approach to rapidly link biochemical activities with genes. Using an ordered array of yeast strains and proteins, we have used this approach to rapidly screen thousands of gene products and identified 16 associated with different biochemical activities. We are also studying tRNA  functional tRNA splicing enzyme, but no apparent corresponding splicing requirement. Our future directions are to improve arrays and extend the functional genomic approach to different classes of activities.

Peter Shrager, Ph. D.
Propagation of electrical signals with high speed and reliability in nerve fibers depends on a complex interaction between neurons and their associated myelinating glial cells. As a result of this interaction, ion channels are clustered at specific sites along the axon. This system is studied in both development and disease. At birth, axons have little myelin, but by the end of the first postnatal week both glial ensheathment and ion channel clustering are at an advanced state. In multiple sclerosis myelin is damaged, and ion channel distributions are disrupted. The immune mechanisms responsible for this pathology are not known. We are studying the molecular mechanisms responsible for these phenomena using electrophysiology, immunocytochemistry, molecular biology, and transgenic manipulations.

Harry A. Stern, Ph. D.
Our research uses atomic-detail computer simulation to examine problems in biochemistry and structural biology. A particular interest is signal transduction by G protein-coupled receptors. We are currently performing mixed quantum mechanical/classical mechanical calculations on opsins in order to investigate the mechanism of spectral tuning in the visual system. We are also working to improve simulations with more accurate potential energy functions, a rigorous method for simulations at constant pH, and faster calculation of electrostatic forces.

Douglas H. Turner, Ph.D.
The research in our group focuses on the forces directing nucleic acid chemistry, with particular emphasis on RNA folding. This chemistry is important for the biochemical basis of life and for design of therapeutics. Nevertheless, much of it is not well understood. Studies of the properties of short oligonucleotides provide insight into the relative contributions of solvent, electronic interactions, and hydrogen bonding in determining the structure, thermodynamics, and dynamics of nucleic acids. This information is incorporated into computer programs to predict the secondary and three-dimensional structure of an RNA. The results from these studies are providing the foundation for a bioinformatics approach to develop deeper interpretations of the many nucleic acid sequences being determined by the Human Genome Project and other sequencing efforts.

Richard Waugh, Ph. D.
In our laboratory we study the mechanical properties of cells and the mechanochemistry of cell adhesion. We are particularly interested in learning about the molecular mechanisms underlying the control of cell deformability and cell adhesion, and the role that mechanical forces and membrane stability play in both the formation and separation of adhesive contacts. Our fundamental approach is to perform mechanical measurements on individual cells or cell pairs to measure response of cells to applied forces or the probability of cell adhesion under controlled conditions. Our main focus is the study of cells in the peripheral vasculature. The deformability of circulating cells and adhesive interactions between cells in the vasculature has relevance to diverse aspects of human physiology ranging from oxygen delivery and hemolytic anemia, to atherosclerosis or immune response and inflammation.

Joseph E. Wedekind, Ph.D.
My lab uses X-ray crystallography and functional analysis to relate macromolecular structure to processes of RNA maturation. The hairpin ribozyme catalyzes a cleavage reaction that uses nucleotides as acid/base catalysts. Our work emphasizes how mutations influence activity, and why some mutations increase kcat/Km. RNA editing is a process whereby a multiprotein 27S editosome deaminates C to U of apoB mRNA. In an effort to develop a working model for RNA editing, we are solving structures of editosome components including intact 27S particles.

David I. Yule, Ph.D.
In exocrine acinar cells regulation of intracellular calcium plays a pivotal role in controlling fluid and protein secretion. Exposure of cells to neurotransmitters and hormones results in a rapid elevation of intracellular calcium. This increase in [Ca2+]i carries complex spatial and temporal information important to the physiology of the acinar cell. Research in our laboratory focuses on gaining a better understanding of the mechanisms which underlie these signaling patterns with a primary goal of relating this knowledge to the physiology and pathophysiology of exocrine cells.