For me, there are too many options. For top-10 player (and former number one) Sirenbrian—aka Florida-based software engineer Brian Smith, who plays FoldIt a couple of hours every night—the signature move is known as the "local wiggle strategy" as well as "walking the backbone," "slice 'n dice" or just "Brianizing". He isolates short segments of the structure and "wiggles" to lower the energy of the locked-off segment.
Former number one player Charles Cusack (screen name "Ferzle"; he's now ranked 23rd), an assistant professor of computer science at Hope College in Holland, Mich., uses a very simple strategy: pull on the protein's backbone, shake, wiggle and repeat. "You just change it a little bit," he says "then let the algorithms do their work."
Staying up late playing protein-folding games may seem a lonely exercise, but chat windows, a wiki, duels and group play make FoldIt into a social environment in which users learn from each other. More than 50,000 individuals have downloaded the application since its release in May. Hundreds actively play it, both alone and in groups, with five or six new gamers joining hourly. Only about half are biologists; the others range from software engineers to historians, from grandmothers to middle-schoolers.
There aren't any prizes, although Baker acknowledges the winners on the FoldIt Web site. Yet for users, it's about more than just the high score. "It is a game that feeds into the actual scientific process," Sirenbrian says. "We might be in the process of developing a new way of analyzing proteins and being of help to people." Thrianya, a grandmother of three with a high school education, says in her user profile, "I love pushing these little bits and pieces around and enjoy very much chatting with people from around the world who like the same sort of thing."
Baker and his team learn from their users, continually on the lookout for moves that users rely on. The most successful routine manipulations will ultimately be codified into Rosetta@home, to make the screen saver more effective.
FoldIt's developers also fly top folders to Seattle to watch them work with the program. Sirenbrian spent a day and a half at FoldIt headquarters in early August. "They interviewed me, videotaped me playing a little bit, and we talked about some of the new tools and features I would like to see added," he says. Among his suggestions were a "squeeze" function, to compress the entire structure (more compact proteins tend to have lower energy) and the ability to control the strength of the wiggle function.
One of Sirenbrian's biggest complaints with FoldIt is that the game is short on instructions. "It is like throwing a lot of tools into the pit," he says, "and seeing what we do with them."
From Baker's perspective, however, that is precisely the point. "We don't know a priori what the best strategies are [for folding proteins], so we create the tools and see what people do with them."
Still, U.W.'s Popović says user input has doubled the number of FoldIt tools since its initial release in May. There's now an annotation tool, which allows users to tag a structure with notes for others to view as well as a tool that rotates structural elements.
Soon, the developers will rely on their users' wisdom to design totally new proteins, which FoldIt has planned for the next release, scheduled to go live sometime in October or November. The new version challenges users to design completely novel proteins that could become tomorrow's HIV vaccines and biofuels. Baker plans to create the 10 best solutions for each challenge in his lab to see how they work.
"We are hoping to define this whole new genre of games, that we would like to call 'scientific discovery games,'" Popović says. "The idea is to find many different places in science where the human ability to problem solve can be directly applied without necessarily requiring somebody to get a PhD in a particular field first."