1. The post-genomic challenge Exploring function across protein families using chemical probes  The CPFM is in early stages of development  Projects focus on studies of protein function (applied genomics)  Participants from: - MCW - Marquette (Biology & Chemistry) - UW-Milwaukee (MFBSC) - UW-Madison (NMRFAM) Long term goal: “Science in Service to Society” Internet2: Enabling Post-Genomic Technology at Marquette Applied research Basic research

2. Internet2: Turning the CPFM into a Collaboratorium

3. Potential Benefits: - Better understanding of biology - Pharmacogenomics & personalized medicine - Treatments for currently untreatable disease - Drugs with fewer side effects - Better understanding of toxicology of pollutants The Promise of Genomics: not yet realized … “The human genome is data not knowledge, and will be useless until we understand what it means.” attributed to Sydney Brenner Genes => Proteins

4. The post-genomic challenge Exploring function across protein families using chemical probes What is the Chemical Proteomics Facility at Marquette? Resources (equipment, software) and people With a mission to:  Enable Chemical Proteomic studies of protein-ligand interactions  Facilitate collaboration across departments and institutions  Provide a better understanding of basic biology  Use science to address social needs  Train scientists and entrepreneurs with social conscience S 3 = Biotechnology with social conscience: science, business, law and engineering

5. Beowulf/Linux cluster facility Modelling lab: remote access to NMRFAM NMR spectrometer lab Fluorescence assay lab CPFM Resources at Marquette: Equipment The post-genomic challenge Exploring function across protein families using chemical probes

6. Internet2: The CPFM as a Collaboratorium Chemistry Biology I2

7. 1) Need High Speed (I2) Connection to MFBSC Viewing of microscopy results at CPFM (imaging) CPFM Client I2

8. Fluorescence imaging as a window to: a)Zebrafish developmental biology b)Drug transport

9. Zebrafish Estrogen Receptors (endocrine disruptor targets) Computationally derived with homology modeling Estrogen receptor … is a protein targeted by endocrine disruptor pollutants (EPA regulations)

10. 2) Need High Speed (I2) Connection to NMRFAM CPFM Client I2

11. Milo Westler, Ph.D. Operations Director NMRFAM Teleconference to NMRFAM: what is NMRFAM?

12. Computational Docking for Drug Design (Dock, Autodock, Caveat & Grid) HIV Protease inhibitor Can use protein structure to design better drugs And to avoid drug metabolism: -Toxic side effects -Drug/drug interactions

13. University of Texas at Austin National Partnership for Advanced Computational Infrastructure IBM Power 4 system 3) Need High Speed (I2) Connection to UTA Marquette’s Beowulf cluster CPFM Client - Ligand-protein docking - Homology modeling - Chemoinformatic analysis of drug properties I2

14. Molecular Legos? Unique enabling of Chemoinformatics at Marquette

15. Summary The post-genomic challenge Exploring function across protein families using chemical probes Internet2: Enabling remote access & collaboration  NMRFAM and MFBSC facilities  Computational resources (UT-Austin; Marquette)  Access to local computational data & tools (chemoinformatics) Databases: endocrine disruptors; optimized drug building blocks S 3 : better drugs, better pollutant screening, basic Biology

16. Current CPFM Projects and Participants Medical College of Wisconsin - Henry Miziorko: Enzymes in the mevalonate biosynthetic pathway: structural and mechanistic studies - Jung-Ja Kim: Structural characterization of molecular motion in NADPH-cytochrome P450 oxidoreducatase Marquette: Chemistry - James Kincaid: Complementary use of NMR & Raman studies to probe substrate binding to cytochrome P450 - Dan Sem : Probing protein-ligand interactions in toxicology and chemical proteomics: methods and application Marquette: Biology - Pinfen Yang: Mechanism of flagellar radial spoke: ligand binding and structural studies of radial spoke protein 2 - Rosemary Stuart: Role of Su e in oligomerizing the F 1 -F 0 ATP synthase complex: structural and binding studies Other collaborators and resources:  UW-Milwaukee: Marine and Freshwater Biomedical Sciences Center  UW-Madison: NMR Facility  UT-Austin: Supercomputer Facility (NSF)