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[ PhD Program: Biophysics Keyword: ]

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NameEmailPhd ProgramResearch InterestsPublications
Allbritton, Nancy email , , , , publications

The overall focus of the laboratory is to quantitatively measure the activity of proteins in cellular signaling networks to understand the relationships of these intracellular pathways in regulating cell health and disease. These networks are composed of interacting proteins and small molecules that work together in a concerted manner to regulate the cell in response to its environment. Despite the importance of these key signaling molecules in controlling the behavior of cells, most of these proteins and metabolites can not be quantified in single cells. There is a need throughout biology for new technologies to identify and understand the molecular circuits within single cells. A research goal is to develop new methods that will broaden the range of measurements possible at the single-cell level and then to utilize these methods to address fundamental biologic questions. We are pursuing this task by bringing to bear diverse techniques from chemistry, physics, biology and engineering to develop new analytical tools to track signal transduction within individual cells. Our research is a multidisciplinary program for the development and application of new analytical methods with two main focus areas: 1) techniques to monitor cellular signaling, and 2) microfabricated cellular analysis systems.

Berkowitz, Max email , , , , publications

We use computational techniques (multiscale molecular dynamics computer simulations) to study interactions of proteins and peptides with membranes and to study interactions of shock waves with membranes of neural cells. Specifically, we study the interaction of antimicrobial peptides with bacterial membranes to understand how they destroy such membranes.  In our study of shock wave interacting with brain tissue we investigate the importance of cavitation effect (collapse of bubbles) created by shock waves. Detailed molecular level knowledge of the processes we investigate using computational methodology is very helpful in understanding processes such as TBI (traumatic brain injury).  The computational methodology we use is also playing now an important role in the filed of drug design.  Member of the Molecular & Cellular Biophysics Training Program.

Bloom, Kerry email , , , , , , publications

Our objective is to understand the dynamic and structural properties of chromosomes during mitosis.  We use live cell imaging techniques to address how kinetochores are assembled, capture microtubules and promote faithful segregation of chromosomes.

Bourret, Bob email , , , , publications

Our long-term goal is to define the molecular mechanisms of two-component regulatory systems, which are utilized for signal transduction by bacteria, archaea, eukaryotic microorganisms, and plants.  Our current focus is to identify and understand the features that control the rates of several different types of protein phosphorylation and dephosphorylation reactions.  The kinetics of phosphotransfer reactions can vary dramatically between different pathways and reflect the need to synchronize biological responses (e.g. behavior, development, physiology, virulence) to environmental stimuli.  Member of the Molecular & Cellular Biophysics Training Program.

Campbell, Sharon email , , , , publications

Current research projects in the Campbell laboratory include structural, biophysical and biochemical studies of wild type and variant Ras and Rho family GTPase proteins, as well as the identification, characterization and structural elucidation of factors that act on these GTPases.  Ras and Rho proteins are members of a large superfamily of related guanine nucleotide binding proteins.  They are key regulators of signal transduction pathways that control cell growth. Rho GTPases regulate signaling pathways that also modulate cell morphology and actin cytoskeletal organization.  Mutated Ras proteins are found in 30% of human cancers and promote uncontrolled cell growth, invasion, and metastasis. Another focus of the lab is in biochemical and biophysical characterization of the cell adhesion proteins, focal adhesion kinase, vinculin, paxillin and palladin.  These proteins are involved in actin cytoskeletal rearrangements and cell motility, amongst other functions. Most of our studies are conducted in collaboration with laboratories that focus on molecular and cellular biological aspects of these problems. This allows us to direct cell-based signaling, motility and transformation analyses. Member of the Molecular & Cellular Biophysics Training Program.

Carter, Charles email , , , , , , publications

Molecular evolution and mechanistic enzymology find powerful synergy in our study of aminoacyl-tRNA synthetases, which translate the genetic code. Class I Tryptophanyl-tRNA Synthetase stores free energy as conformational strain imposed by long-range, interactions on the minimal catalytic domain (MCD) when it binds ATP.  We study how this allostery works using X-ray crystallography, bioinformatics, molecular dynamics, enzyme kinetics, and thermodynamics. As coding sequences for class I and II MCDs have significant complementarity, we also pursuing their sense/antisense ancestry.  Member of the Molecular & Cellular Biophysics Training Program.

Cheney, Richard email , , , , , , publications

Our goal is to understand the fundamental cell biology underlying processes such as neurodevelopment, angiogenesis, and the metastasis of cancer cells.  Most of our experiments focus on molecular motors such as myosin-X and on the finger-like structures known as filopodia.  We generally utilize advanced imaging techniques such as TIRF and single-molecule imaging in conjunction with mammalian cell culture.  We also  use molecular biology and biochemistry and are in the process of developing a mouse model to investigate the functions of myosin-X and filopodia.   We are looking for experimentally driven students who have strong interests in understanding the molecular basis of dynamic cellular processes such as filopodial extension, mechanosensing, and cell migration.

Costello, Joe email , , , , , publications

The main research project is to determine the role of intercellular junctions in normal development, cell aging and cataract formation in human and animal lenses.

Dokholyan, Nikolay email , , , , , publications

The mission of my laboratory is to develop and apply integrated computational and experimental strategies to understand, sense, and control misfolded proteins, and uncover the etiologies of human diseases. UNDERSTAND: We are working toward understanding of the protein misfolding diseases, such as Lou Gehrig’s disease and cystic fibrosis.. Other areas of interest include HIV, Graft versus Host disease (fatal autoimmune response to bone marrow transplant), and understanding and developing new drugs for pain. SENSE: We are working toward developing genetically-encoded proteins that bind and report rare/intermediate conformations of target molecules (proteins and RNA). CONTROL: We are working toward developing genetically-encoded proteins that control target proteins with light and/or drugs. We have developed novel approach for drug activation/deactivation of kinases, and light-activatable protein to manipulate protein function with light. We are working toward extending these approaches to other classes of proteins and on multiplexing, whereby we selectively activate/control several distinct cellular pathways via targeting several proteins simultaneously.

Elston, Timothy email , , , , publications

The Elston lab is interested in understanding the dynamics of complex biological systems, and developing reliable mathematical models that capture the essential components of these systems. The projects in the lab encompass a wide variety of biological phenomena including signaling through MAPK pathways, noise in gene regulatory networks, airway surface volume regulation, and understanding energy transduction in motor proteins. A major focus of our research is understanding the role of molecular level noise in cellular and molecular processes. We have developed the software tool BioNetS to accurately and efficiently simulate stochastic models of biochemical networks

Erie, Dorothy email , , , , publications

The research in my lab is divided into two main areas – 1) Atomic force microscopy and fluorescence studies of protein-protein and protein-nucleic acid interactions, and 2) Mechanistic studies of transcription elongation. My research spans the biochemical, biophysical, and analytical regimes.

Gladfelter, Amy email , , , , , publications

We study large multinucleate cells such as fungi, muscle and placenta to understand how cells are organized in time and space.  Using quantitative live cell microscopy, biochemical reconstitution and computational approaches we examine how the physical properties of molecules generate spatial patterning of cytosol and scaling of cytoskeleton scaffolds in the cell cycle.

Goldstein, Bob email , , , , , , publications

We address fundamental issues in cell and developmental biology, issues such as how cells move to specific positions, how the orientations of cell divisions are determined, how the mitotic spindle is positioned in cells, and how cells respond to cell signaling – for example Wnt signaling, which is important in development and in cancer biology. We are committed to applying whatever methods are required to answer important questions. As a result, we use diverse methods, including methods of cell biology, developmental biology, forward and reverse genetics including RNAi, biochemistry, biophysics, mathematical and computational modeling and simulations, molecular biology, and live microscopy of cells and of the dynamic components of the cytoskeleton – microfilaments, microtubules, and motor proteins. Most experiments in the lab use C. elegans embryos, and we have also used Drosophila and Xenopus recently. C. elegans is valuable as a model system because of the possibility of combining the diverse techniques above to answer a wide array of interesting questions. We also have a project underway to develop a new model system for studying how cellular and developmental mechanisms evolve, using little-studied organisms called water bears. Rotating graduate students learn to master existing techniques, and students who join the lab typically grow their rotation projects into larger, long term projects, and/or develop creative, new projects.

Griffith, Jack email , , , , , , publications

We are interested in basic DNA-protein interactions as related to – DNA replication, DNA repair and telomere function.  We utilize a combination of state of the art molecular and biochemical methods together with high resolution electron microscopes.

Hahn, Klaus email , , , , , , , , , publications

Dynamic control of signaling networks in living cells; Rho family and MAPK networks in motility and network plasticity; new tools to study protein activity in living cells (i.e., biosensors, protein photomanipulation, microscopy). Member of the Molecular & Cellular Biophysics Training Program and the Medicinal Chemistry Program.

Jacobson, Ken email , , , publications

Structure, dynamics and function of viral domains in biomembranes.  Photomanipulation and traction mapping applied to the migration of single cells. Investigation of the mechanochemical basis of cell oscillations using systems biology approaches coupled with experiments.

Jarstfer, Michael email , , , , publications

The Jarstfer lab uses an interdisciplinary approach to solve biological problems that are germane to human health.   Currently we are investigating the structure of the enzyme telomerase, we are developing small-molecules that target the telomere for drug discovery and chemical biology purposes, and we are investigating the signals that communicate the telomere state to the cell in order to control cellular immortality. We are also engaged in a drug/chemical tool discovery project to identify small molecules that control complex social behavior in mammals.  Techniques include standard molecular biology and biochemistry of DNA, RNA, and proteins, occasional organic synthesis, and high throughput screening.

Johnson, Gary L. email , , , , publications

Spatio-temporal regulation of signal relay systems in cells using live cell fluorescence imaging and targeted gene disruption of signaling proteins to define their role in development, physiology and pathophysiology.

Kash, Thomas email , , , , , , publications

Emotional behavior is regulated by a host of chemicals, including neurotransmitters and neuromodulators, acting on specific circuits within the brain. There is strong evidence for the existence of both endogenous stress and anti-stress systems. Chronic exposure to drugs of abuse and stress are hypothesized to modulate the relative balance of activity of these systems within key circuitry in the brain leading to dysregulated emotional behavior. One of the primary focuses of the Kash lab is to understand how chronic drugs of abuse and stress alter neuronal function, focusing on these stress and anti-stress systems in brain circuitry important for anxiety-like behavior. In particular, we are interested in defining alterations in synaptic function, modulation and plasticity using a combination of whole-cell patch-clamp physiology, biochemistry and mouse models.  Current projects are focused on the role of a unique population of dopamine neurons in alcoholism and anxiety.

Ke, Hengming email , , , , publications

Our research focuses on the structure and function of medically important proteins from the crystallographic approach.  The current topics include cycolphilin, calcineurin, heat shock protein 90 (hsp90), and cyclic nucleotide phosphodiesterase.

Kier, William email , , , publications

I am interested in the comparative biomechanics of marine invertebrates.  In particular, I study the functional morphology of musculoskeletal systems, the structure, function, development and evolution of muscle, and invertebrate zoology, with particular emphasis on the biology of cephalopod molluscs (octopus and squid).  My research is conducted at a variety of levels and integrates the range from the behavior of the entire animal to the ultrastructure and biochemistry of its tissues.

Ko, Ching-Chang email , , , , publications

Ko’s laboratory has focused on bone regeneration using biomaterials and biomechanical approaches. The on-going project is to develop a new synthetic process for biomimetic bone nanocomposites. The new biomaterial and its scaffolds are under development for stem cell-mediated bone regeneration. Biomechanical principles that regulate mineral crystallization are incorporated with the biomaterial approach to translate research outcomes to clinical usage (e.g., immediately loaded dental implants). My lab is also interested in understanding reverse engineering principles of bio-mienralization.

Kuhlman, Brian email , , , , publications

We use a combination of experimental and computational methods to redesign protein-protein interactions.  The potential applications for this technology include enhancing protein therapeutic and creating new tools to study signaling pathways.

Laederach, Alain email , , , , , publications

The Laederach Lab is interested in better understanding the relationship between RNA structure and folding and human disease. We use a combination of computational and experimental approaches to study the process of RNA folding and in the cells. In particular, we develop novel approaches to analyze and interpret chemical and enzymatic mapping data on a genomic scale. We aim to fundamentally understand the role of RNA structure in controlling post-transcriptional regulatory mechanisms, and to interpret structure as a secondary layer of information (http://www.nature.com/nature/journal/v505/n7485/full/505621a.html).  We are particularly interested in how human genetic variation affects RNA regulatory structure. We investigate the relationship between disease-associated Single Nucleotide Polymorphisms occurring in Human UTRs and their effect on RNA structure to determine if they form a RiboSNitch.

Lai, Samuel email , , , , , , , , publications

Our dynamic group are broadly involve in three topics: (i) prevention of infectious diseases by harnessing interactions between secreted antibodies and mucus, (ii) immune response to biomaterials, and (iii) targeted delivery of nanomedicine.  Our group was the first to discover that secreted antibodies can interact with mucins to trap pathogens in mucus.  We are now harnessing this approach to engineer improved passive and active immuniation (i.e. vaccines) at mucosal surfaces, as well as understand their interplay with the mucosal microbiome.  We are also studying the adaptive immune response to polymers, including anti-PEG antibodies, and how it might impact the efficacy of PEGylated therapeutics.  Lastly, we are engineering fusion proteins that can guide targeted delivery of nanomedicine to heterogenous tumors and enable personalized medicine.

Lee, Andrew email , , , , publications

We study protein structure and dynamics as they relate to protein function and energetics. We are currently using NMR spectroscopy (e.g. spin relaxation), computation, and a variety of other biophysical techniques to gain a deeper understanding of proteins at atomic level resolution.  Of specific interest is the general phenomenon of long-range communication within protein structures, such as observed in allostery and conformational change.  A. Lee is a member of the Molecular & Cellular Biophysics Training Program.

Lentz, Barry email , , , , publications

The regulatory role of platelet membrane phosphatidylserine in blood coagulation; mechanism of protein-mediated membrane fusion in secretory processes and virus infection.  Director of the Molecular & Cellular Biophysics Training Program.

Li, Bo email , , , , publications

Our research focuses on the discovery and design of new gene-encoded bioactive small molecules from bacteria.  We are interested in understanding enzymes involved in their biosynthesis, their therapeutic mechanisms of action, and implications in health and diseases, in particular with respect to the human microbiome.  This work is driven by intensive development of new metabolomics and genomics technologies.  We subsequently manipulate and engineer these biosynthetic pathways to make new and improved molecules as potential therapeutics such as antibiotics.

Liu, Rihe email , , , , publications

The research interests of the Liu Lab are in functional proteomics and biopharmaceuticals. Currently we are working on the following projects:  (1). Using systems biology approaches to decipher the signaling pathways mediated by disease-related proteases such as caspases and granzymes and by post-translationally modified histones. We address these problems by performing functional protein selections using mRNA-displayed proteome libraries from human, mouse, Drosophila, and C. elegans. (2). Developing novel protein therapeutics and nucleic acid therapeutics that can be used in tumor diagnosis, treatment, and nanomedicine. We use various amplification-based molecular evolution approaches such as mRNA-display and in vivo SELEX to develop novel single domain antibody mimics on the basis of very stable protein domains or to generate aptamers on the basis of nuclease-resistant nucleic acids, that bind to important biomarkers on the surface of cancer cells. We further conjugate these biomarker-binding affinity reagents to small molecule drugs or nanoparticles for targeted delivery of therapeutic agents. (3). Identifying the protein targets of drugs or drug candidates whose action mechanisms are unknown. We combine molecular proteomic and chemical biology approaches to identify the protein targets of drugs whose target-binding affinities are modest.

Lockett, Matthew Ryen email , , , publications

Research in the Lockett group focuses on the development of analytical model systems to: i) chemically modify the surface of thin films, and study chemical and biochemical reactions occurring on those surfaces; ii) study drug metabolism in an environment that closely mimics the human liver; iii) measure tumor invasion in an environment that closely mimics human tissue. /  / While these problems require techniques found in analytical chemistry, biochemistry, molecular biology, bioengineering, and surface science we are particularly interested in the technologies that allow us to quantitatively measure reactions and analytes.

Macdonald, Jeffrey email , , , publications

Dr. Macdonald is the Founder and Scientific Director of the new Metabolomic Facility and Co-Scientific Director of the joint UNC/NCSU/NOAA Marine MRI facility at Pivers Island near Beaufort NC. Dr. Macdonald’s research goal is to combine metabolomics and tissue engineering and apply these tools to quantitative biosystem analysis.

Maddox, Amy Shaub email , , , , , , , publications

My research philosophy is summed up by a quote from Nobelist Albert Szent-Gyorgyi: “Discovery is to see what everybody has seen and to think what nobody has thought.” My lab studies the molecular and physical mechanisms of cell shape change during cytokinesis and tissue biogenesis during development. Specifically, we are defining how cells ensure proper alignment and sliding of cytoskeletal filaments, and determining the shape of the cell throughout division. To do so, we combine developmental biology, cell biology, biochemistry, and quantitative image analysis.

Maddox, Paul S. email , , , publications

My research program is centered on understanding fundamental aspects of cell division. During cell division, complex DNA-protein interactions transform diffuse interphase chromatin into discrete mitotic chromosomes, condensing them several thousand fold to facilitate spatial segregation of sister chromatids. Concomitantly, kinetochores form specifically at centromere regions of chromosomes and regulate force-producing interactions with microtubules. While these processes are absolutely required for genomic stability, the in vivo mechanisms of chromosome and kinetochore assembly remain unsolved problems in biology. I investigate 1) the spatiotemporal regulation of mitotic chromosome assembly, and 2) the molecular basis of centromere specification. To do so, I will combine biochemical approaches with high-resolution light microscopy of live cells, whole organisms, and in vitro systems.

Manis, Paul B. email , , , , publications

We are interested in the cellular and network mechanisms of sensory information processing in the central nervous system, with an emphasis on the neural substrates for hearing. We study functional network organization, synaptic function, the roles of ion channels and cellular excitability, and short and long-term synaptic plasticity, in the auditory brainstem and auditory cortex.  Experimentally, we use patch clamp methods in brain slices, optogenetics and laser scanning photostimulation, multiphoton imaging, and computational neuroscience (modeling), in normal and transgenic mouse models. The lab also has collaborative projects related to schizophrenia (prefrontal cortex; Dr. Patricia Maness, UNC) and connectomics (cochlear nucleus and MNTB; Dr. George Spirou, WVU).

McGinty, Robert email , , , , , publications

The McGinty lab uses structural biology, protein chemistry, biochemistry, and proteomics to study epigenetic signaling through chromatin in health and disease.  Chromatin displays an extraordinary diversity of chemical modifications that choreograph gene expression, DNA replication, and DNA repair – misregeulation of which leads to human diseases, especially cancer. We prepare designer chromatin containing specific combinations of histone post-translational modifications. When paired with X-ray crystallography and cryo-electron microscopy, this allows us to interrogate mechanisms underlying epigenetic signaling at atomic resolution.

Meissner, Gerhard email , , , , publications

The goal of the laboratory’s research is to define the structure and function of an intracellular Ca2+ release channel in skeletal and cardiac muscle, using molecular biological and electrophysiological methods and by creating mutant mice.

Pearce, Ken email , , , , , publications

We are a comprehensive, collaborative group with a primary focus on lead and early drug discovery for oncology and epigenetic targets and pathways.  Our research applies reagent production, primary assay development, high-throughput screening, biophysics, and exploratory cell biology to enable small molecule drug discovery programs in solid partnership with collaborators, both within the Center for Integrative Chemical Biology and Drug Discovery and across the UNC campus.  We apply small molecule hit discovery to highly validated biochemical targets as well as phenotypic cell-based assays.  Our methods include various fluorescence-based readouts and high content microscopy.  Examples of some of our collaborative small molecule discovery programs include, inhibition of chromatin methyl-lysine reader proteins, hit discovery for small GTPases such as K-Ras and Gaq, inhibitors of inositol phosphate kinases, inhibitors of protein-protein interactions involving CIB1 and MAGE proteins, and several cell-based efforts including a screen for compounds that enhance c-Myc degradation in pancreatic cancer cells.  In addition, we are developing a DNA-encoded library approach for hit discovery to complement traditional high-throughput screening.  Our ultimate goal is discovery of new chemical probes and medicines for exploratory biology and unmet medical needs, respectively.

Pielak, Gary J. email , , , , , publications

My graduate students and I use the formalism of equilibrium thermodynamics and the tools of molecular biology and biophysics to understand how nature designs proteins.

Riordan, John email , , publications

The primary research focus is the structure, function and biosynthetic processing of membrane proteins which provide permeability pathways through the membranes of cells. Much of the current work is concentrated on the ion channel protein, CFTR (cystic fibrosis transmembrane conductance regulator) which is absent or dysfunctional in patients with cystic fibrosis. To elucidate the molecular mechanisms of CFTR function, we study single channel properties by electrophysiological techniques, enzymatic activity and physical interaction with other cellular molecules. A major objective of studies with the purified molecule is to obtain 3-dimensional structure information so that small molecules capable of recognizing features of its surface shape can be synthesized and used to modulate its folding and activity.

Sancar, Aziz email , , , , , publications

We have three main areas of research focus: (1) Nucleotide excision repair: The only known mechanism for the removal of bulky DNA adducts in humans. (2) DNA damage checkpoints:  Biochemical pathways that transiently block cell cycle progression while DNA contains damage.  (3) Circadian rhythm:  The oscillations in biochemical, physiological and behavioral processes that occur with the periodicity of about 24 hours.

Slep, Kevin email , , , , , , , publications

Our lab examines cytoskeletal dynamics, the molecules that regulate it and the biological processes it is involved in using live cell imaging, in vitro reconstitution and x-ray crystallography.  Of particular interest are the microtubule +TIP proteins that dynamically localize to microtubule plus ends, communicate with the actin network, regulate microtubule dynamics, capture kinetochores and engage the cell cortex under polarity-based cues.

Sondek, John email , , , , , , publications

Our laboratory studies signal transduction systems controlled by heterotrimeric G proteins as well as Ras-related GTPases using a variety of biophysical, biochemical and cellular techniques. Member of the Molecular & Cellular Biophysics Training Program.

Thompson, Nancy email , , publications

The immune system is a network of interacting biological cells. The molecular events that lead to the activation and regulation of these cells often occur at the cell surface. However, little is known about the arrangement, motions and interactions of the participating cell-surface molecules. To examine these phenomena, we construct model cell membranes on planar supports from purified or synthesized molecules.  Recently developed techniques in laser-based fluorescence microscopy can then be employed to examine the behavior of select fluorescently labeled molecules at or near the supported planar membranes.  This research is significant not only in the basic understanding of the immune system, but also in other areas of cell-cell communication and cell membrane biophysics, in the physics of two-dimensional fluids, and in biotechnology.

Waters, Marcey email , , publications

Our research focuses on several different aspects of biomolecular recognition, including (1) protein post-translational modifications, (2) protein-nucleic acid interactions, and (3) protein-protein interactions that are important in a number of different biological areas, including epigenetics and cancer.  We use bio-organic chemistry combined with peptide design and biophysical chemistry to study these interactions and to develop new tools for inhibition and/or sensing of these biomolecular interactions.

Weeks, Kevin email , , , , , , publications

The Weeks group invents novel chemical microscopes for understanding the structure and function of RNA and then applies these technologies to leading, and previously intractable, problems in biology. Most projects in the laboratory span fundamental chemistry or technology development and ultimately lead to practical applications in virology (especially HIV), next-generation structure analysis, drug design, and understanding RNA structure in living cells.  Collectively, this work has led to extensive recognition of graduate student colleagues in the laboratory.

Williams, David C. Jr. email , , , , publications

The overall objective of our research is to understand the connection between structure of protein-DNA complexes, protein dynamics and function.  We currently focus on the methyl-cytosine binding domain (MBD) family of DNA binding proteins.  The MBD proteins selectively recognize methylated CpG dinucleotides and regulate gene expression critical for both normal development and carcinogenesis.  We use a combination of NMR spectroscopy and biophysical analyses to study protein-DNA and protein-protein complexes involving the MBD proteins.  Building on these studies, we are developing inhibitors of complex formation as potential molecular therapeutics for b-hemoglobinopathies and cancer.

Wolfenden, Richard email , , publications

Enzymes allow organisms to channel the flow of matter to their own advantage, allowing some reactions to proceed rapidly compared with other reactions that offer no selective advantage to the organism. After a substrate is bound at an enzyme’s active site, its half-life is usually a small fraction of 1 s. Rapid turnover is necessary if any enzyme is to produce a significant rate of reaction at the limited concentration (<10(-5) M) at which enzymes are present within the cell. Many enzymes are known to have evolved to work nearly as efficiently as is physically possible, with second order rate constants that approach their rates of encounter (10(9) M(-1)s(-1) with the substrate in solution. How rapidly would biological reactions occur if an enzyme were not present? Until recently, some reactions were known to require several years, and everyday experience suggests that some reactions are slower still. The survival of paper documents and ancient ships for long periods under water implies that the glycosidic bonds of cellulose, for example, are very resistant to hydrolysis in the absence of cellulases that catalyze their hydrolysis. Why would one wish to know the rate of a biological reaction in the absence of an enzyme? That information would allow biologists to appreciate what natural selection has accomplished in the evolution of enzymes as proficient catalysts and would enable chemists to compare enzymes with artificial catalysts produced in the laboratory. Such information would also be of value in considering the design of enzyme antagonists: the greater the rate enhancement that an enzyme produces, the greater is its affinity for the altered substrate in the transition state compared with its relatively modest affinity for the substrate in the ground state. That principle has furnished a basis for the design of transition state analogues, extremely powerful inhibitors that resemble the transition state and take advantage of that special affinity. Examples have now been discovered for enzymes of every class, including inhibitors that are already used to control hypertension, the spread of HIV, the maturation of insects and the growth of weeds. By allowing snapshots of enzymes in action, transition state analogues have also provided valuable tools for investigating enzyme structures and mechanisms, most recently that of the peptide bond forming center of the ribosome. Those enzymes that produce the largest rate enhancements and transition state affinities should offer the most sensitive targets for inhibitor design. Particularly remarkable are those enzymes that act as simple protein catalysts, without the assistance of metals or other cofactors. To determine the extent to which one such enzyme, human uroporphyrinogen decarboxylase, enhances the rate of substrate decarboxylation; we examined the rate of spontaneous decarboxylation of pyrrolyl-3-acetate. Extrapolation of first-order rate constants measured at elevated temperatures indicates that this reaction proceeds with a half-life of 2.3 x 10(9) years, approaching the age of the Earth. This enzyme shows no significant structural or sequence homology with yeast orotidine 5′-monophosphate decarboxylase, another cofactorless enzyme that catalyzes a very slow reaction. To uncover the mechanisms of action of these remarkable molecules, we are studying these and other enzymes by kinetic and structural methods, site-directed mutation and the study of model reactions. In addition to more traditional methods, these projects make extensive use of new methods that include high-field NMR, isothermal calorimetry, and kinetic experiments in water and other solvents in sealed tubes at very high temperatures.

Yeh, Elaine email , , , publications

The site of microtubule attachment to the chromosome is the kinetochore, a complex of over 60 proteins assembled at a specific site on the chromosome, the centromere. Almost every kinetochore protein identified in yeast is conserved through humans and the organization of the kinetochore in yeast may serve as the fundamental unit of attachment. More recently we have become interested in the role of two different classes of ATP binding proteins, cohesions (Smc3, Scc1) and chromatin remodeling factors (Cac1, Hir1, Rdh54) in the structural organization of the kinetochore and their contribution to the fidelity of chromosome segregation.

Zhang, Qi email , , , , publications

Our laboratory is focusing on developing and applying solution-state NMR methods, together with computational and biochemical approaches, to understand the molecular basis of nucleic acid functions that range from enzymatic catalysis to gene regulation. In particular, we aim to visualize, with atomic resolution, the entire dynamic processes of ribozyme catalysis, riboswitch-based gene regulation, and co-transciptional folding of mRNA. The principles deduced from these studies will provide atomic basis for rational manipulation of RNA catalysis and folding, and for de novo design of small molecules that target specific RNA signals. Research program in the laboratory provides diverse training opportunities in areas of spectroscopy, biophysics, structural biology, computational modeling, and biochemistry.