Many of the forefronts in chemistry lie at the interface with biology. One half of Pitt's Chemistry research groups work at this dynamic boundary. Current activities target:
Nitric Oxide Dynamics in Proteins
Proteins provide the structural elements as well as the catalytic machines of biology. Why do only a fraction of a percent of random amino acid sequences form proteins? What is the physical origin of cooperative long-range interactions in molecules like hemoglobin? How do biomolecules regulate the flow of electrons and ions that transform sunlight and carbon dioxide into sugars? What structure and function information can be gleaned from spectroscopic probes of biomolecules? All of these questions are being addressed in our research groups.
Protein Folding Dynamics
The Walker and Asher groups are using electronic and vibrational spectroscopy to probe the dynamics of protein folding. Their research is examining the interplay of protein substructures on different time and length scales, as they might control protein stability and drug binding. Walker's group is also probing the dynamics of NO binding and release within blood proteins and neuropeptides. The Asher group is examining the early dynamics of protein folding and unfolding. It is probing the breakage and formation of amide hydrogen bonds as well as the time evolution of peptide backbone conformational changes. The binding of small molecules to proteins often triggers a cascade of events.
Dynamics of Host-Guest Systems
The Waldeck and Walker groups are using electronic and vibrational spectroscopy to build a "movie" of how these smaller molecules navigate the big protein, recognize their binding sites, and bind. For example, Waldeck's group is using experimental studies that probe the motion of synthetic substrate-receptor complexes to understand how a complex's structure determines its flexibility.
Theory plays a substantial role in the developing quantitative physical descriptions of the structure-function relations that arise in biology. For example, Coalson's group is building models to describe the flow of ions through trans-membrane channels using a combination of atomistic simulation methods and macroscopic mass-transport methods. In collaboration with Prof. Michael (see bioanalysis section, below), Coalson's group is simulating diffusion processes in complex biochemical environments. These studies are intended to elucidate the migration of neurotransmitters through brain tissue, as probed experimentally with microdialysis techniques.
Molecular Torsion Balance for
Evaluating Intramolecular Forces
Grabowski's group uses photoacoustic calorimetry to measure bond dissociation energies in systems duch as coenzyme B-12. Asher's group examines the structure of proteins and how different amino acid contacts, hydrogen bonds and salt bridges, determine the molecular structure and dynamics. While biology occurs in the condensed phase, gas phase electronic spectroscopy can address important open mechanistic questions. Pratt's group is using high-resolution spectroscopy to examine the fundamental intermolecular interactions associated with base pairing in nucleic acids, the hydrophobic effect, and catalysis in serine protease. The Wilcox group synthesizes molecular machines to evaluate the forces controlling biomolecule function.
Metallation of Peptides
Biology provides a vast array of natural products of potential use - from medicine to materials science. The groups of Curran, Shepherd, Wilcox and Wipf are drawing upon specific known natural products, as well as proposed biological interaction mechanisms, to synthesize materials of value. For example, Curran, Shepherd, and Wipf are developing synthetic routes to molecules of potential pharmaceutical value. Wilcox and Shepherd are using lessons from nature to design organic and inorganic molecules that interact with biomolecules, thus controlling their function. Shepherd's research group is making small molecule metal complexes of iron or ruthenium that can scavenge excess NO that is produced by white blood cells during toxic shock. His research students are also making binuclear ruthenium and platinum metallo-drugs that target the DNA of tumor cells for coordination-induced cell death or that carry NO to DNA targets for release during photodynamic therapy. Floreancig's group is fighting the evolution of bacterial resistance by working toward the creation of new antibacterial agents, and is developing a design and synthesis of structurally simplified glycoprotein (P-gp) inhibitors.
Molecular engineering of water soluble
Transmembrane proteins are a very important class of proteins for which very few X-ray crystal structures are available. The Schafmeister group will explore molecular engineering approaches using synthetic chemistry and molecular biology to construct water-soluble transmembrane proteins that can be used for X-ray structure determination. The methodology that we develop using the model transmembrane protein bacteriorhodopsin will then be applied to G-protein coupled receptors.
The Koide group is undertaking three different approaches to study and regulate gene expression. Chemical syntheses of antitumor agents will enable regulation of tumor-related genes. Combinatorial library compounds that the group is synthesizing will be tested for gene regulation of important processes such as stem cell differentiation. Chemical sensor molecules are being synthesized to visualize gene expression using fluorescence spectroscopy.
SEMs of Electrode for Detecting Dopamine (left)
and Glutamate Microsensor (right)
Knowing what biochemical species exist in a given point in space at a given instant in time may be essential to determine biological function. Walker is developing near field optical and chemically derivitized force probes that allow 10 nm-scale resolution of the membrane surface properties. Michael's group is developing new electrochemical and separations based techniques to probe brain function by monitoring neurotransmitter dynamics in the extracellular space of the central nervous system. Weber's group designs novel sensors for organic acids, biologically active metal ions, and drugs based upon molecular recognition strategies. Chemistry and instrumentation are being developed that enables biologists to search for and to find peptide messenger molecules in the brain. Asher is using molecular recognition on derivitized hydrogels for chemical sensing. Walker's group is developing the atomic force microscope (AFM) as a diagnostic tool for the surgical pathologist. They are correlating biomechanical and elastic changes in tissue with pathologic changes in tissues.
Scanning electrochemical microscopy of pores
The Petoud group is preparing luminescent lanthanide complexes are designed to have specific properties for use as: luminescent probes for time-resolved measurements in cell biology and bio-assays in aqueous solution (clinical diagnostic, genomic screening and drug discovery). This research involves research involves several types of chemistry and analytical techniques including organic, inorganic and supramolecular design and syntheses and detailed photophysical, kinetic, and thermodynamic investigations.
The Amemiya group is interested in understanding the ion- and molecular-transport processes through biomembrane nanostructures, e.g., ion-channel pores (0.2-10 nm) and lipid domains (100-500 nm). They are trying to detect the transported species with small electrochemical sensors and to obtain chemical images of biomembranes by scanning the sensors parallel to the membrane surface (this technique is called scanning electrochemical microscopy; SECM).
Distances between specifically attached
spin labels measured to study local structures
Saxena’s group studies the relationship of protein dynamics and interactions to their overall functions. The primary tool used is multidimensional Fourier transform electron spin resonance spectroscopy which provides a unique opportunity for resolving large separations between domains in proteins as well as local dynamics over a wide timescale. Current research involves the elucidation of molecular interactions and conformational dynamics that dictate the heat shock response.
Biological Chemistry in the Department of Chemistry at the University of Pittsburgh has a rich tradition of interdisciplinary success. Each of the above scientists is also likely to have strong connections to local hospitals or medical schools, pharmaceutical companies, national centers for structural biology, and a wide range of interdepartmental collaborations. Whether you work in bioanalytical, bioorganic, bioinorganic, or biophysical chemistry, you will belong to a vibrant community of dedicated researchers with the highest scientific aspirations.
Please contact us to hear more recent updates on this research at Pitt and the opportunities that await you.
Graduate Study in Biological Chemistry
Department of Chemistry
219 Parkman Avenue
University of Pittsburgh
Pittsburgh, PA 15260