Chemical Biology considers the fundamental chemical principles that govern all biological systems. The UM Chemistry department is home to an exciting multidisciplinary program at the interface of Chemistry and Biology. Synthesis, measurement and theory of biological molecules are important components. Particular areas of expertise are Biological Catalysis, Biomolecular Structure & Function, Chemical Genetics, Imaging & Sensing, Metallo-Biochemistry, RNA Biochemistry, Synthetic Biology & Nanotechnology, Theory & Simulation, and Metallo-Neurochemistry. Laboratory rotations allow students to explore their individual areas of interest before choosing their thesis mentor. Students may also participate unique, NIH-funded UM training programs like Chemistry & Biology Interface, Molecular Biophysics, Cellular Biotechnology, Pharmacological Sciences and Microfluidics in Biomedical Sciences; these inter-disciplinary programs can include internships in industrial settings. We also offer a dynamic Future Faculty Program funded by the US Department of Education.
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Understanding how nature catalyzes the chemical reactions that occur in living organisms is a problem central to the field of chemical biology. We are using combinations of physical, chemical, and genetic approaches to investigate the reaction mechanisms of protein and RNA enzymes. Members of the department are studying a wide range of biologically important chemical reactions, including the modification of proteins by lipid, carbohydrate and other chemical groups, the generation of free radicals by enzymes, and how RNA molecules are specifically cleaved and processed in the cell.
Figure 1. Fluorine, an abiological element, can often substituted for hydrogen in proteins, although not as easily as this illustration might suggest! Fluorinated analogs of hydrophobic amino acids closely mimic the shape of their hydrocarbon counterparts and so can generally be introduced into a protein with minimal perturbation to its structure. Fluorinated proteins and peptides can be designed and used for fluorine NMR to investigate their interactions with their biological targets.
Biological macromolecules have precise three-dimensional structures that are essential determinants of their biological function. The exploration of the relationship between structure and function is key to understanding the chemical reactivity and molecular recognition properties of biological molecules. At Michigan, interests include determination of the high-resolution structure and molecular dynamics of macromolecules using spectroscopic, crystallographic and computational methods; investigation of the molecular determinants of catalytic activity and molecular recognition; exploitation of macromolecules for the development of therapeutic agents, biocatalysts, biomaterials and biosensors, study of the role of natural and manufactured particles in cell inflammation and toxicity, and examination of macromolecular localization and motion in living cells.
Figure 1. Crystal Structure of PRORP1. Cartoon depiction of the PRORP1 domain arrangements: PPR domain (residues 95 to 292; red), central domain (residues 328 to 357 and 534 to 570; yellow) and metallonuclease domain (residues 358 to 533; blue)
Figure 2. Investigation of the structure and dynamics of membrane proteins, electron-transfer metalloprotein and amyloid proteins using NMR and other biophysical techniques. The helical structure of amyloid-beta intermediate and the role of ganglioside in the amyloid-beta toxicity and Alzheimer’s disease are determined.
n chemical genetics, cell-permeable, transfected and microinjected compounds are used as molecular probes to study intracellular processes, such as gene expression and post-translational modifications. Natural products often provide lead structures as the starting points for these agents. At Michigan, compounds with exquisite specificity for the treatment of genetic diseases have been obtained through the use of both rational design and combinatorial chemistry.
Imaging and sensing molecules is a central problem in areas ranging from environmental to biomedical sciences. Researchers in the Chemistry department, in collaboration with the Schools of Medicine, Public Health, and Colle of Engineering, are pioneering the design and synthesis of ultra-small devices for the detection of minute amounts of clinically relevant analytes and pathogens to probe biological pathways and to diagnose and treat diseases. On a more fundamental level, the biological, physico-chemical and catalytic properties of biomolecules are studied one single molecule at a time; this provides high-resolution insight into biological function without averaging.
Figure 1. Single-molecule microscopy to study position and dynamics in live bacteria. One of our interests is the pathogenetic pathway in Vibrio cholerae, agent of the cholera disease, which is regulated by interactions of the membrane-bound transcription activator, TcpP, with the toxT gene. This involves (A) super-resolution localization and imaging, (B) single-particle tracking and (C) novel methods for data acquisition and analysis.
Non-protein coding RNAs are involved in a multitude of cellular processes ranging from protein synthesis, regulation and processing of genetic information to viral defense through RNA interference. At Michigan, research on RNA Biochemistry includes ribozyme catalysis, RNA structure and dynamics, as well as the dissection of the role of RNA:protein complexes required for translation, pre-messenger RNA splicing, and gene regulation by riboswitches and RNA silencing at both the ensemble and single molecule level.
It is estimated that one-third of all proteins contain a tightly bound metal ion. Metallo-Biochemistry explores the roles of metal ions in biological samples. At Michigan, interests range from the synthesis of small-molecule mimics for enzyme active sites to the structural, spectroscopic, and enzymologic characterization of metal sites in proteins and nucleic acids. A central theme guiding these studies is the effort to relate metal-ion structure and reactivity to biological function. The faculty at Michigan is also developing novel tools to analyze the function, localization and concentration of intracellular metal ions.
Figure 1. The de novo designed protein Hg(II),Zn(II)[CSL9CL23H]3 is a functional analogue of the human carbonic anhydrases, catalyzing CO2 hydration and ester hydrolysis at very fast rates. Related structures containing copper are functional nitrite reductases.
The prospect of building nanoscale molecular circuitry from the ground up to mimic the complex non-linear feedback loops of biological systems has recently spawned the field of synthetic biology. At Michigan, DNA and protein building blocks are being assembled into increasingly complex structural scaffolds that are decorated with enzymatic activities to translate biochemical pathways and biological actuators into controllable nanodevices; and single molecule and super-resolution microscopes are used to perform quality and performance control of the ever-expanding nanodevice toolkit.
Figure 1. Two-color reconstructions of three individual DNA origami tiles using a single molecule fluorescence super-resolution technique called PAINT; from left to right, a substrate (red) deposited on the origami surface (green) is visibly lost through chemical cleavage (scale bars, 50 nm).
The modeling of chemical and biophysical processes is playing an increasingly important role in informing and enhancing our understanding of the systems studied in chemical biology. At Michigan, computer simulations using complex models for proteins, nucleic acids, their ligands and complexes are employed in examine chemical and physical transformations under investigation through experimentation. These studies use large-scale simulations on local and national resources and examine phenomena such as protein folding, single molecule RNA manipulation, enzyme catalysis and small molecule binding to biological receptors.
Distinct features of human neurodegenerative diseases, such as Alzheimer’s disease, are accumulation of misfolded proteins (e.g., amyloid-beta) and metal ion dyshomeostasis. Interaction and reactivity of metal ions with misfolded proteins have been suggested to be involved in neurodegneration. These aspects in disease development, however, have not been clearly elucidated. In order to advance this understanding and contribute to drug discovery,
Figure 1. Design of chemical tools for studying the involvement of metal-associated amyloid-beta species in the pathogenesis of Alzheimer’s disease, as well as discovery of new drugs for the disease.