Protein Structure, Dynamics and Design (PSDD) Initiative

Structure. Virtually all of the chemical processes in biology involve proteins. It is reasonably easy using tools of molecular biology to determine the linear sequence of amino acids that comprise a protein. The three dimensional structures of proteins and protein/DNA complexes can be determined using x-ray crystallography and/or nuclear magnetic resonance (NMR) spectroscopy. Advances in computing, protein expression and purification and crystallization over the last decade have reduced the time required to determine the structure of a novel protein from years to months.

Dynamics. The goals of dynamics are to elucidate bond breaking and bond making steps in biochemical reactions, model reaction intermediates, map real time structural changes in enzymes, receptors, transcription factors and channels as they function and trace pathway(s) of protein folding and roles of chaperones and posttranslational modifications in folding. Related to this it be possible to design small molecular inhibitors to fit to specific sites in proteins.

Design. In the future, it should provide possible to engineer highly specific reactions (e.g., catalytic antibodies), to develop peptides that can act as agonists or antagonists of receptors and to design proteins that can interact with cell-specific binding sites for drug delivery.

Strategic Planning. A working group* of the EBS has developed a strategic plan for developing the PSDD Initiative. The group reviewed the state of the art of protein chemistry at the university of Michigan, performed a SWAT analysis and submitted a report to the Associate Dean for Research in June, 2006. It was the consensus of the committee that the University of Michigan Medical School has an outstanding record in protein chemistry and continues to have broad strengths in all aspects of the studies of proteins.

There are also many other talented protein chemists and enzymologists in Chemistry and Medicinal Chemistry. Faculty is these departments and Biological Chemistry and Pharmacology work on enzymes, cytoskeletal proteins, transporters, receptors, intramolecular adapters, hormones and transcription factors. Thus, building in this area would represent building on a widely acknowledged strength both within the Medical School and on campus. Structural biology is an area that Biological Chemistry, Pharmacology and LSI have developed with the hiring of four crystallographers during the past three years.

The new Chemical Biology Ph.D. Program should also enhance protein chemistry at UM. Macromolecular modeling in association with structural studies is a focus area of Bioinformatics. There are already many local high-end facilities for performing protein structural studies. Other facilities available to U-M faculty include a synchrotron beamline being built at Argonne and a 900 MHz NMR located at MSU. The report outlined an ambitious plan for the PSDD Initiative. The major elements of the plan are as follows:

To develop the infrastructure in protein chemistry at UM including:

  1. Upgrading local X-ray instruments.
  2. Purchasing a crystal visualization system.
  3. Providing support for the LS-CAT beam lines (Argonne).
  4. Providing support for a high throughput cloning, expression and purification developed in conjunction with Center for Structural Biology.
  5. Providing support for the purchase of an 800 MHz shielded NMR with a cryoprobe in conjunction with hiring an NMR structural biologist.
  6. Supporting the purchase of Cryo-EM equipment in conjunction with hiring a Cryo-EM structural biology faculty member.
  7. Upgrading chemical biology custom synthetic capabilities.

To support hiring of new faculty in key areas of protein chemistry including faculty in:

  1. Structural Biology of proteins and protein complexes
  2. Chemical Biology
  3. Epi-genetics
  4. Redox Biochemistry
  5. Protein Folding/Chaperone Function

*W. Smith (Biol. Chem., working group chair), Jay Hess (Pathology), Ben Margolis (Int. Med., Biol Chem.), Janet Smith (Biol. Chem., LSI), Roger Sunahara (Pharmacol.), Ray Trievel (Biol. Chem.), Shaomeng Wang (Int. Med.), Erik Zuiderweg (Chem., Biol. Chem, Biophysics).