Student Projects for UMass Chemistry 423 Spring 2012

Spring 2012 Chem423 Team Projects: Protein-ligand Complexes for Understanding Drug and Disease Mechanisms

Project InstructionsProject Instructions

1. Topics and 1 green scene: Sandbox pages displaying initial structure and one green scene due at class workshop 2/27/12

Teams of 4 people will be assigned, to include both chemistry and chemical engineering majors on most teams. You may request one teammate by emailing the TA by Feb 17.

Select an available topic (not already chosen by another team) from the list or find a simple protein-ligand complex (eg protein-drug, nucleic acid-drug, or protein-DNA) with a known structure in the pdb that interests your team. For any topic not on the list, email Prof Thompson to get approval: send the pdb code for the complex and briefly explain the disease connection or why it is interesting. Add your topic to the team list at Sandbox 423.

Start your assigned sandbox page: Find the pdb id for your protein-ligand complex in the Protein Data Bank. In your assigned sandbox page click"edit this page" (top) and follow the directions to insert your rotating structure on your page. Describe and illustrate with a green scene the secondary structure of your protein.

2. Project near-final draft, due 1 week before presentation. Presentation dates will be assigned when topics are chosen. Prof Thompson will provide suggestions for improvements (you may also request feedback earlier, once you have at least one green scene with text describing it in all sections. Your proteopedia page should be organized into the following 4 required sections, with each team member responsible for one of sections a-d of the team project. Each section should have its own jmol window. Provide an interesting and nontechnical description in words, and illustrate points about the complex with green scenes. Be concise: the written description should not extend beyond the jmol window. Do not include any copyrighted figures. All sections must be written in your own words with citations to your sources, following the format in the example below. Make it interesting and accessible to a non-scientist! a. Introduction

Introduce the protein function, how it is related to a disease, and what is important about the ligand in the complex. Make a green scene suitable for the Molecular Playground: an attractive and informative illustration of the protein complex with an interesting short caption describing it.

b. Overall structure

Describe the overall structure of your protein in words and make "green scenes" to illustrate your points. What elements of secondary structure are present (ie 5 alpha helices and 2 beta strands) and how are they organized? Additional description and green scenes could illustrate the polar/nonpolar distrubution of amino acids (is the inside of the barrel polar or nonpolar?), packing of amphipathic elements, etc.

c. Drug binding site

Describe features of the drug or ligand binding site in words and make "green scenes" to illustrate your points. Show the interactions that stabilize binding of this molecule to the protein (ie H bonds).

d. Additional features

Describe and use green scenes to illustrate additional features of the protein. What you do here depends on what information is available. If a structure of the protein-substrate complex is available, you could compare protein interactions with the substrate vs. with the drug. If the drug is a transition state inhibitor, explain and illustrate that (eg include a reaction scheme with structures of the substrate, transition state and product -- but don't borrow a published scheme).

e. Credits -- at the end list who did which portion of the project:

Introduction -- name of team member

Overall structure -- name of team member

Drug binding site -- name of team member

Additional features -- name of team member

f. References This will include the published paper that describes your structure (the reference associated with your pdb code). You will get much of your information about specific interactions to look for and highlight in the structure from this reference (which is much easier than trying to find these on your own with no guidance!).

'3. In-class presentations on assigned dates."

ExampleExample

This is a complex between a macromolecule and its ligand (but this ligand is not a drug) that illlustrates the use of green scenes:

spinqualitylabelsall models Aspartate receptor ligand binding domain (1wat) Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image

Asp Receptor Ligand-binding domain

Overall structure

The ligand binding domain of the aspartate receptor () ) is a dimer of two 4-helix bundles that is shown here with the bound. In this the N and C termini are at the bottom of the structure; this is where the connections to the transmembrane helices have been truncated.

Ligand binding site

Interactions that stabilize ligand binding include hydrogen bonding from Tyr149 and Gln152 backbone carbonyls and Thr154 sidechain OH to the and hydrogen bonding from the sidechain nitrogens of Arg64, Arg69, and Arg73 to the two .

References

Help EditingHelp Editing

Hint: Ctl-click or right-click on links below and select "Open Link in New Window"

Start with Help in the navigation box on the left. Some things I've found useful:

• Follow the step-by-step written Primer.

• For step-by-step instructions on creating example scenes, try Proteopedia:DIY:Scenes.

• For editing help, try Help:Editing. Guidelines for avoiding plagiarism are listed here: Proteopedia:Guidelines for Ethical Writing.

• You can use the edit button on any page to find out how other users created effects that you see in the text (not the scenes).

[Wikimedia cheat sheet]

[General help with Wiki editing], plus more [Wiki Text examples]

Some of the above are for help editing Wikipedia pages, but the syntax is mostly the same. Proteopedia ADDS protein stuff to the WikiMedia markup language, which powers both WEB sites.