Protein Videogame

Biologists Enlist Online Gamers

Players of a new game will design HIV vaccines and other proteins.

By Katherine Bourzac

Proteins are the workhorses of biology. Among their many functions, proteins speed chemical reactions, enable blood cells to recognize intruding viruses, and copy DNA. The potential payoffs of making proteins that don't exist in nature, such as those needed for HIV vaccines or as catalysts for more-efficient biofuel production, are huge. But making proteins to meet a specific need can be difficult.

Now a leading protein researcher has teamed up with computer scientists to create an online game for developing useful protein structures. David Baker, a leading protein scientist at the University of Washington, says that players will help his lab design new vaccines and make enzymes for repairing DNA in diseased tissues.

For years, biochemists have reengineered naturally occurring proteins by growing them in viruses and single-celled organisms in a process called directed evolution. But researchers need to start with a preexisting protein, which makes it difficult to develop proteins with totally new functions. In a major step forward, Baker recently demonstrated the first algorithm for building novel, functioning enzymes from scratch. But while proteins built from the ground up may have chemical properties unmatched by anything in nature, they aren't particularly efficient.

The game, called Foldit, is part of Baker's vision for the future of protein engineering. His algorithms are good at the nitty-gritty of generating completely novel protein sequences for a particular purpose. But humans, who are better at seeing the big picture than computers are, could improve computer-designed proteins by playing the game.

Proteins are made up of long strings of amino acids that are folded up into complex three-dimensional tangles with many subregions. The function of a protein is dependent on this three-dimensional structure. One pocket might be ideal for grabbing on to another protein, for example. Other parts of the protein may play a purely supportive, structural role, holding the molecule together. Baker's new method for creating novel proteins begins with the active sites. Once they're in place, structural concerns, especially how tightly packed the protein is, determine whether the design is feasible. Figuring out the best way to hold together the active sites is a complicated search problem that requires a lot of processing power. There are a myriad of possibilities, but most won't work.

Since 2005, Baker's lab has relied on the computing power of Internet users who've installed a program that searches through protein designs. About 200,000 people around the world run his Rosetta@home program when their computers would otherwise be idle. As Rosetta@home runs, it displays the protein structures that it's processing as a screen saver. Some users staring at the structures, which look like large tangles of multicolored string, told Baker that they could see how to make the structure better--where to tuck in a loose end, or how to pull the structure together tighter--but were frustrated because they had no way to provide input.

When the computer doesn't know what the best next step is, it changes the structure randomly. Baker says that he began to wonder whether people working with computers can solve a hard problem that computers can't solve alone.

Baker enlisted Zoran PopoviÐ"‡, a game designer at the University of Washington, to create the protein-folding game. This task presented PopoviÐ"‡'s design team with an unusual challenge. "For standard games, the goal is known, and the game play is designed to guide the player toward it," says PopoviÐ"‡. Mario needs to save the princess, collecting as many coins as he can on the way. But in the case of the protein game, the end goal is unknown. "The ultimate protein configuration, and how best to get there, are not known," PopoviÐ"‡ says of Foldit.

The first several levels of Foldit are designed to teach players what good proteins look like and how to manipulate them using the tools of the game. Players

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