1. Computers, Chemistry, and Biology in a First Year Seminar Julie B. Ealy Assistant Professor of Chemistry Pennsylvania State University Lehigh Valley American Chemical Society August 2005 Washington, DC

2. First Year Seminar at PSU Required of all freshman Skill development Academic integrity Sense of community Active and collaborative learning Technology 8 months in preparation

3. Molecular Modeling – Spartan Pro –utilize computer generated software that permits 3D visualization of molecular images that enhances understanding of molecular structure Organic bases of RNA – 3D structure, formula, hydrogen bonds 20 amino bases – name, abbreviation 21 nucleotides of cDNA for the spike glycoprotein of SARS – identify complementary RNA – aa Build a beta sheet – 3 amino acids Build an alpha helix – 8 amino acids

4. Atoms, Formulas, Bonds

5. Guanine - Cytosine

6. Hydrogen bonds, Formula

7. Amino Acids Below are the twenty amino acids. Amino acids are the monomer building blocks of proteins. 1) Fill in the name of the amino acid in the space below the amino acid, followed by the three-letter amino acid abbreviation, then the one letter symbol. (These are found on p.7 of this exercise.) 2) Write the formula in the second space beneath the name as you view the molecule from left to right. An example of the first one would be: occhnhch2oh. The order could be somewhat different than written. If you are unsure about the identity of an element, look at the amino acid molecule in the window displayed at the right in Spartan Pro.

8. Beta Sheet In Spartan Pro choose file, new, and peptide (on the right). Make sure that  (beta) sheet is checked near the bottom right. Choose any amino acid and click on the screen. Orient the amino acid so the N-H (amine group) of the amino acid is on the left. The C=O (carbonyl) group should be on the right. Choose another different amino acid. Click on the end of the yellow hydrogen of the carbonyl group of the amino acid on the screen. Choose a third different amino acid. Click on the yellow hydrogen bond of the 2nd amino acid. There should now be three amino acids on the screen.

9. Carbonyl and Amine Groups, Peptide bonds and Unit Red – Circle the carbonyl groupsHow many carbonyl groups?_______ Blue – Circle the amine groupsHow many amine groups?_______ Green – Circle the side chains of the amino acids. Use the figure in this section as a guideline and draw an arrow to the peptide bonds on your polypeptide. How many peptide bonds are there?_______ Draw a “square” around one peptide unit on you polypeptide. In the first part of this section a  (beta) sheet was chosen to build polypeptide. The beta strand on the screen represents the secondary structure of a polypeptide.

10. Alpha Helix In Spartan Pro, choose new, peptide,  helix. Choose 8 different amino acids (except glycine) always joining the amino acid to the hydrogen of the carbonyl group. The polypeptide will need to be rotated to find the hydrogen. Rotate the alpha helix until you can “see” down through the middle. Choose Build, minimize. The polypeptide chain will move and an energy value will be reported on the lower right corner of the screen. When you chose “minimize” the polypeptide moved and tweaked and settled into a more stable arrangement. The lower an energy value is, the more stable the structure.

11. Main Proteinase of SARS

12. Magnified View of Main Proteinase with Residues Use the “magnifier” icon to make the protein bigger so you can see the amino acid letter and number better. Rotate the protein and identify four amino acids in different locations. Fill in the blanks with the letter abbreviation and amino acid number. Write out the complete name of the amino acid, also.

13. Interactive Docking with Streptavidin and Biotin What is seen on the screen is streptavidin, a bacterial protein, complexed with biotin (purple), a ligand (which in this case is a fancy name for a molecule). The structure of the complex was determined in 1989 by Weber, et al. Biotin is actually vitamin H and is necessary for metabolism and growth in humans. Biotin binds tightly to streptavidin and makes the complex one of interest in research. If the binding of biotin to streptavidin can be understood better, it will aid in the design of new drugs and ligands for proteins and nucleic acids.

14. Identification of a Binding Site for a Drug What has happened is that a potential binding site for a ligand has been identified. If this was a different protein several potential binding sites would result. Click on the square to the left of g_pocket 1 to make the square blue. The binding site that has been identified is the approximate location that biotin binds to streptavidin.

15. Identification of Neighboring Atoms around the Biotin The neighboring atoms around the pocket define where biotin will dock itself. The green crosses that are displayed define the pocket.

16. The Pocket for Biotin The amino acids (in yellow) define the space around the pocket where biotin will fit.

17. Biotin Docked into the Defined Pocket The ligand, biotin, samples the defined space to find the lowest and most stable energy configuration in conjunction with the protein, streptavidin.

18. Energy Values Sampled by Biotin The plot is all the energy values that resulted as biotin sampled the space that was defined by the amino acids - the neighboring atoms - of streptavidin. The lowest and most stable energy value is found at, -56.8. In the tutorial on amino acids and secondary structures – alpha helices and beta sheets – were minimized. The structures “tweeked” as they achieved the most stable configuration and repulsive interactions were minimized. An energy value resulted after the minimization.

19. What Did Students Say about the Computer Technology?  The thing that astonished me was that there are approximately 1256 amino acids that make up the spike glycoprotein. Now that I have seen what a single amino looked like, then to think of 1256 of them all linked to each other (for the SARS spike glycoprotein) is amazing.  The Spartan Pro program is a great tool to generate a visual aid as a backup to what we are discussing in class. Because my science background is limited, comprehension of structures is difficult without a picture as reinforcement.  The” fieldtrips” to the chemistry labs were nice in that it allowed us to visualize and manipulate many of the chemical aspects of diseases and drugs.  The thing that most impressed me was the programs we got to use to visualize the virus and the amino acids.

20. Acknowledgements Adrienne Dorward – Penn State student Penn State University, Lehigh Valley Research Development grant