Screenshot of the Foldit application showing a folding puzzle in progress
|Developer(s)||University of Washington
(Center for Game Science, Department of Biochemistry)
|Initial release||May 8, 2008|
|Development status||Active (Perpetual beta)|
(Microsoft Windows, Mac OS X, Linux)
|Available in||English, Russian, French
|Type||Puzzle video game, Protein folding|
|License||Freeware for academic and non-profit use |
Foldit is an online puzzle video game about protein folding. The game is part of an experimental research project, and is developed by the University of Washington's Center for Game Science in collaboration with the UW Department of Biochemistry. The objective of the game is to fold the structure of selected proteins to the best of the player's ability, using various tools provided within the game. The highest scoring solutions are analysed by researchers, who determine whether or not there is a native structural configuration (or native state) that can be applied to the relevant proteins, in the "real world". Scientists can then use such solutions to solve "real-world" problems, by targeting and eradicating diseases, and creating biological innovations.
David Baker, a protein research scientist at the University of Washington, is responsible for beginning the Foldit project. Seth Cooper was the lead game designer. Prior to the project's commencement, Baker and his laboratory co-workers relied upon another research project, Rosetta, to predict the native structures of various proteins, using special computer protein structure prediction algorithms. The project was eventually extended to utilize the processing power of user's personal computers, by developing a distributed computing program; Rosetta@home. The Rosetta@home program was made available for public download, and was designed to display progress of a particular protein being worked on at the time, as a screensaver. The results of the program's prediction routines are sent to a central project server, for verification.
Some users of Rosetta@home became frustrated with the program when they realised they could see ways of solving the protein structures themselves but could not interact with the program. When Baker realised that humans could have considerable potential over computers attempting to solve protein structures, he approached David Salesin, a fellow computer scientist, and Zoran Popović, a game designer studying at the same university, to help conceptualize and build an interactive program that would both appeal to the public and assist in their efforts to find the native structures of proteins - a game.
Since 2008, the Foldit project has participated in Critical Assessment of Techniques for Protein Structure Prediction (CASP) experiments, submitting its best solutions to targets based on unknown protein structures. CASP is an international experiment, which aims to assess existing methods of protein structure prediction, and highlight research that may be more productive toward solving protein structures.
Protein structure prediction is important in several fields of science, including bioinformatics, molecular biology, and medicine. Successful identification of the structural configuration of natural proteins enables scientists to study and understand proteins better. This can lead toward the creation of novel proteins by design, advancements in the treatment of diseases, and the development of solutions for other real-world problems, such as invasive species, waste, and pollution.
The process by which living beings create the primary structure of proteins, protein biosynthesis, is reasonably well understood, as is the means by which proteins are encoded as DNA. Determining how the primary structure of a protein turns into a functioning three-dimensional structure—how the molecule "folds"—is more difficult; the general process is known, but protein structure prediction is computationally demanding.
Similar to Rosetta@home, David Baker and his team of co-workers aim to use Foldit as a means of discovering native protein structures faster, through a combination of crowdsourcing and distributed computing. However, there is a greater emphasis on crowdsourcing and community collaboration with the Foldit project. Other methods, such as virtual interaction and gamification were added, creating a unique and innovative project environment with the potential to greatly assist the cause.
Virtual Interaction 
Foldit attempts to apply the human brain's natural three-dimensional pattern matching and spatial reasoning abilities to help solve the problem of protein structure prediction. Current puzzles are based on well-understood proteins; by analysing the ways in which humans intuitively approach these puzzles, researchers hope to improve the algorithms employed by existing protein-folding software.
Foldit provides a series of tutorials in which the user manipulates simple protein-like structures and a periodically updated set of puzzles based on real proteins. The application displays a graphical representation of the protein's structure which the user is able to manipulate with the aid of a set of tools.
Rather than just building a useful science tool, the developers of Foldit focused on designing a program that adopted the concept of gamification; the aim was to make the program more appealing and engaging to a public audience, in order to attract more people to the cause of protein folding. This was especially true for those people that did not have a scientific education or background.
As the structure is modified, a "score" is calculated based on how well-folded the protein is, and a list of high scores for each puzzle is maintained. Foldit users may create and join groups, and share puzzle solutions with each other; a separate list of group high scores is maintained.
- In 2011, players of Foldit helped to decipher the crystal structure of the Mason-Pfizer monkey virus (M-PMV) retroviral protease, an AIDS-causing monkey virus. While the puzzle was available to play for a period of three weeks, players produced an accurate 3D model of the enzyme in just ten days. The problem of how to configure the structure of the enzyme had stumped scientists for 15 years.
- On January, 2012, Scientific American reported that the Foldit gamers achieved the first crowdsourced redesign of a protein. The protein is an enzyme which catalyses the Diels-Alder reactions widely used in synthetic chemistry. A team including David Baker in the Center for Game Science at University of Washington in Seattle computationally designed this enzyme from scratch but found the potency needing improvement. The Foldit players reengineered the enzyme by adding 13 amino acids and increased its activity by more than 18 times.
Future Development 
The game’s toolbox is primarily for the design of protein molecules. The game creator announced the plan to add the chemical building blocks with organic subcomponents to enable the Foldit players to design small molecules by 2013.
See also 
- Howard Hughes Medical Institute "Protein-folding game taps power of worldwide audience to solve difficult puzzles" Eurekalert!, August 4, 2010
- Bourzac, Katherine. "Biologists Enlist Online Gamers" Technology Review, May 8, 2008
- Bohannon, John. "Gamers Unravel the Secret Life of Protein" Wired (magazine), April 20, 2009
- Hickey, Hannah. "Computer game's high score could earn the Nobel Prize in medicine" University of Washington, May 8, 2008
- Marshall, Jessica (January 22, 2012). "Online Gamers Achieve First Crowd-Sourced Redesign of Protein". Scientific America. Retrieved February 22, 2012.
- Khatib, F.; Dimaio, F.; Cooper, S.; Kazmierczyk, M.; Gilski, M.; Krzywda, S.; Zabranska, H.; Pichova, I. et al. (2011). "Crystal structure of a monomeric retroviral protease solved by protein folding game players". Nature Structural & Molecular Biology 18 (10): 1175. doi:10.1038/nsmb.2119.
- Praetorius, Dean. "Gamers Decode AIDS Protein That Stumped Researchers For 15 Years In Just 3 Weeks" The Huffington Post, September 19, 2011
- Eiben, Christopher; Siegel, Justin; Bale, Jacob; Cooper, Seth; Khatib, Firas; Shen, Betty; Players, Foldit; Stoddard, Barry; Popovic, Zoran; Baker, David (2012). "Increased Diels-Alderase activity through backbone remodeling guided by Foldit players". Nature Biotechnology 30 (2): 190–192. doi:10.1038/nbt.2109. PMID 22267011. Retrieved February 22, 2012.
- Hersher, Rebecca (April 13, 2012). "FoldIt game’s next play: crowdsourcing better drug design". nature.com. Retrieved April 16, 2012.