2009-02-16T21:09:56Z

Tim Herman:

Dr. Herman received his B.S. in chemistry from the University of Nebraska in 1972 and his Ph.D. in biochemistry from Oregon State University in 1976. He pursued post-doctoral studies in molecular biology at Harvard Medical School from 1977-1980. He joined the biochemistry faculty at the Medical College of Wisconsin in 1980, and for the next 18 years, taught graduate and medical students while directing research programs in areas ranging from the synthesis of chemically cleavable biotin-labeled nucleotide analogs to the development of novel approaches to structure-based drug design. In 1997, he began working with the MSOE Rapid Prototyping Center to apply this additive manufacturing technology to the production of physical models of proteins. He officially joined the Milwaukee School of Engineering in 1998, as Director of the newly-created Center for BioMolecular Modeling. Dr. Herman's current research interests are focused in two areas: the application of rapid prototyping technology to the production of physical models of molecular structures, and science education research projects designed to measure the impact of physical and computer-based models of molecular structures on student learning.

*[[User:Tim Herman/Workbench]]

2009-01-21T15:19:43Z

Tim Herman:

=A SMART Team Molecular Story - Madison West High School Project of β2-Adrenergic Receptor=

<applet load='2rh1.pdb' size='250' frame='true' align='left' scene='Hoelzer_Sandbox/Building_our_model/7'/>
<swf width="350" height="300">http://myweb.msoe.edu/~hoelzer/proteopedia%20test.swf</swf>

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==Abstract for Our Project==

G protein-coupled receptors (GPCRs) are the largest family of integral membrane proteins coded by the human genome. GPCRs are important for signal transduction and share the general structural characteristic of a plasma membrane receptor with seven transmembrane segments. More than 50% of human therapeutics act on a member of the GPCR family of proteins. One example of a GPCR targeted by pharmaceutical companies is the β2-adrenergic receptor. Adrenergic receptors are found throughout the body and are triggered by the hormone epinephrine (also known as adrenaline, hence the name adrenergic). When epinephrine binds to the receptor, it causes a slight conformational change within the receptor. This change then triggers activation of a G-protein --- proteins that bind GTP and are coupled to the receptor on the cytoplasmic side of the receptor --- causing dissociation of the G-protein from the receptor. Through the transfer of GTP, G-protein activates an enzyme that converts ATP into cyclic AMP, which induces a response within the cell (for example, muscle contraction if the receptor is located on a muscle cell). When this signal transduction event functions normally in the body, it helps regulate heart rate and blood pressure and is important for the “fight or flight” response. It is important medically to be able to manipulate these functions in cases of high blood pressure or heart failure through the use of beta blockers, a medicine designed to bind to adrenergic receptors, thus inhibiting the binding of epinephrine, and resulting in a lack of effect of the hormone on the body. We have used rapid prototyping technology to model the interaction of the human β2-adrenergic receptor with the beta blocker, carazolol. The structure is dominated by seven alpha helices and is representative of the structure of GPCRs. By modeling the β2-adrenergic receptor, we hope to better understand GPCRs as well as understand the mechanism of hormone/drug binding, which will aid in developing better drug treatments.

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==Creating the Physical Model of the β2-adrenergic receptor==

<applet load='2rh1.pdb' size='400' frame='true' align='left' caption='Madison West SMART Team Model - β2-Adrenergic Receptor' scene='Hoelzer_Sandbox/Building_our_model/8'/>

Virtually any image of a protein that can be created in the computer environment of RP-RasMol, can be converted into a physical model of the protein using rapid prototyping technology.

To design our model of the β2-adrenergic receptor, we used the atomic coordinates for this structure as reported in the pdb file 2rh1, from the Ray Stevens laboratory at the Scripps Research Institute. Our model represents <scene name='Hoelzer_Sandbox/Image_1/1'>amino acids 29-230 and 263-342 </scene>. Starting with a cpk-colored, spacefilled representation of the protein, we simplified this image by converting it to an <scene name='Hoelzer_Sandbox/Image_2/1'>alpha-carbon backbone representation</scene>. We colored the seven trans-membrane alpha helices green --- connected by loops that we colored gray. We then displayed four sidechains <scene name='Hoelzer_Sandbox/Spacefilled_4/7'>(Phe 193, Trp 286, Phe 289, and Phe 290)</scene> involved in the binding of a beta-blocker, and colored them blue. The beta-blocker, <scene name='Hoelzer_Sandbox/Spacefilled_4/6'>Carazolol</scene>, was then added in a ball-and-stick format, colored orange. The <scene name='Hoelzer_Sandbox/Spacefilled_4/8'>three cholesterol molecules </scene> resolved in this structure, bound to the outside surface of the protein, were added and displayed in a ball-and-stick format, colored red. Finally, <scene name='Hoelzer_Sandbox/Spacefilled_4/9'>the N-terminal end </scene>of the protein was colored blue, and <scene name='Hoelzer_Sandbox/Spacefilled_4/10'>the C-terminal end </scene>was colored magenta.

A ply file describing this final structure was exported from RP-RasMol and sent to the MSOE Center for BioMolecular Modeling, where it was constructed from plaster powder, using a color ZCorp 3D printer.

We started our physical model of the β2-adrenergic receptor by opening the pdb file [[2rh1|2rh1.pdb]] in the protein viewing software Rasmol. We started by opening our pdb file in Rasmol as a spacefill model <scene name='Hoelzer_Sandbox/Building_our_model/8'>(STEP ONE)</scene>. Our SMART Team wanted to focus on the binding portion of the receptor so we only displayed residues 29-230 and 263-342 in backbone format <scene name='Hoelzer_Sandbox/Building_our_model/2'>(STEP TWO)</scene>. Next, we colored the alpha helices green, the turns gray, the first amino acid on the N-terminal end blue, and the last amino acid on the C-terminal end magenta. <scene name='Hoelzer_Sandbox/Building_our_model/3'>(STEP THREE)</scene>. Then we added the cholesterol ligands located on the side of the seven helix portion of the protein. We displayed them in ball and stick format and colored them red <scene name='Hoelzer_Sandbox/Building_our_model/4'>(STEP FOUR)</scene>. One of the most important portions of our model is the beta blocker Carazolol which we displayed in ball and stick format and colored orange <scene name='Hoelzer_Sandbox/Building_our_model/5'>(STEP FIVE)</scene>. The last step was adding the main sidechains involved in the binding of the beta blocker. We displayed Phe 193, Trp 286, Phe 289, and Phe 290 in ball and stick format and colored them cyan <scene name='Hoelzer_Sandbox/Building_our_model/6'>(STEP SIX)</scene>. Once our model designs were complete in Rasmol, we added monitor lines to help support the model for building and saved the 3D file for printing <scene name='Hoelzer_Sandbox/Building_our_model/7'>(STEP SEVEN)</scene>. Our model was built by the Center for BioMolecular Modeling at the Milwaukee School of Engineering where they are able to use rapid prototyping technology to build any model designed in the computer environment.

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==Our Poster and Presentations==

[[Image:Madison West SMART Team at ASBMB.jpg|Madison West SMART Team| 350px]]
[[Image:Madison West SMART Team at Scripps.jpg|Madison West SMART Team| 350px]]
[[Image:Madison West SMART Team Poster - 2008.jpg|Madison West SMART Team| 350px]]

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We were able to present our project, poster, and our physical models at the 2008 ASBMB meeting in San Diego, CA. The poster was presented several other times including at the Medical College of Wisconsin and at the Scripps Research Institute. During our visit to Scripps, we met David Goodsell and Art Olsen, two molecular illustrators for the Molecular Graphics Laboratory at the institute.

==MSOE Center for BioMolecular Modeling and SMART Teams==
[[Image:Center for BioMolecular Modeling Logo.jpg|left|200px]]
[[Image:Smart Teams photo 5.jpg|right|120px]]

SMART Teams (Students Modeling A Research Topic)is a science outreach program developed by the MSOE Center for BioMolecular Modeling. In this program, teams of high school students work with a local resarch lab to design and build a physical model of a protein that is being investigated by the lab. The goal of the SMART Team program is to introduce students to the real world of scince --- as it exists in a local research lab. This developement of this program was supported by grants from the NIH-NCRR SEPA program (Science Education Partnership Award) and an HHMI Precollege Science Education Award. For more information about this program, visit the CBM web site at www.rpc.msoe.edu/cbm.