Foldit: Playing a Game While Solving Protein Structures *

Abstract

Figuring out the tertiary structure of a protein is often done using powerful computer programs, such as Foldit. In Foldit, an interactive computer game, users can investigate how the amino acids in a protein prefer to interact with each other, and the space around them, in specific ways that lead to an overall stable protein structure. Users compete with each other to create the most stable tertiary structures for a given protein, or the best "solution." In this way, in September of 2011 users of Foldit were actually able to solve the structure of an enzyme critical for causing AIDS, specifically an enzyme that is important for the maturation and proliferating of the virus. Enzymes like this one are the focus for anti-viral drug efforts. Users solved the enzyme's structure within three weeks, while it had puzzled scientists for a decade. You can read more about this discovery in the citation below. Hopefully Foldit users will continue to help with medical breakthroughs along these lines.

So what makes one "solution" better than another "solution"? In this science project, you will investigate how one proposed tertiary structure for a protein is more or less stable than another proposed tertiary structure. For this science project, after downloading the Foldit game and creating a user account, we recommend that you complete all, or at least most, of the 32 "Intro Puzzles." This will give you a good idea of the strategy used to solve more complex puzzles. You can then explore the "Science Puzzles" and "Contests" (Note: You need to manually download the latter inside the game).

For the "Science Puzzles" for which the protein structure is known, try to match your solution to the "Guide" (the known protein structure). For the harder "Science Puzzles" and all of the "Contests," you can join a Foldit Group to share "Solutions" with other people. Anyone can make a group, or you can ask to join a group on the in-game chat. You could even look online for the solved structure of a similar protein, such as by searching the RCSB Protein Data Bank. When solving protein structures and comparing solutions, think about the following:

• How well are the hydrophobic residues hidden within the protein? Are there many yellow "exposeds"?
• How compact is the structure? Are there a lot of "voids"?
• Are there many stable hydrogen bonds? Are any anti-parallel beta sheets stabilized with hydrogen bonds?
• Are all the sidechains in good positions?

Even if you're new to Foldit, by thinking about these questions and having some patience you'll be folding proteins like a pro in no time!

Credits

Teisha Rowland, PhD, Science Buddies

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Bibliography

To do this science project, you will need to download the Foldit program, which you can find here:

• Foldit: Solve Puzzles for Science. (n.d). Retrieved September 28, 2011, from http://fold.it/

Here are a few websites that will help you start gathering information about Foldit, how to use it to solve protein structures, and more on protein structures:

• Foldit: Solve Puzzles for Science. (n.d.). The Science Behind Foldit. Retrieved September 28, 2011, from http://fold.it/portal/info/science
• Foldit: Solve Puzzles for Science. (n.d.). Top Groups. Retrieved September 30, 2011, from http://fold.it/portal/groups
• Foldit Wiki. (n.d.). Strategy. Retrieved September 30, 2011, from http://foldit.wikia.com/wiki/Strategy
• NCBI. (n.d.). Section 3.1 Hierarchical Structure of Proteins. Retrieved October 5, 2011, from http://www.ncbi.nlm.nih.gov/books/NBK21581/
• RCSB Protein Data Bank. (n.d.). Biological Macromolecular Resource. Retrieved September 14, 2011, from http://www.rcsb.org/pdb

Here you can read about the recent medical breakthrough of solving an HIV enzyme structure using Foldit:

• Coren, M. J. and Fast Company. (2011, September 20). Foldit Gamers Solve Riddle of HIV Enzyme within 3 Weeks. Scientific American. Retrieved September 22, 2011, from http://www.scientificamerican.com/article.cfm?id=foldit-gamers-solve-riddle
• Khatib, F. et al. (2011, September 18). Crystal structure of a monomeric retroviral protease solved by protein folding game players. Nature Structural & Molecular Biology. Retrieved September 22, 2011, from http://www.nature.com/nsmb/journal/vaop/ncurrent/full/nsmb.2119.html

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