Gamers Unravel the Secret Life of Protein: ”

The key to how any protein works is its three-dimensional shape, determined by all the ways its atoms interact. Trying to push two atoms closer when they want to repel is like holding magnets together when they’re oriented the wrong way. You can force them, but nature prefers configurations that follow the path of least resistance. In a simple molecule, that path is pretty clear: Water—H₂O—is hydrogen-oxygen-hydrogen balanced perfectly in a V-shape at a 104.4-degree angle. This push and pull is inevitable. Physics is destiny.

The Challenge
The online game Foldit is designed to reveal the shortcuts nature uses to weave a tangle of amino acids, like the one shown here, into a protein. Players click to move pieces around until they fit.

But the bigger the molecule, the more complex these negotiations become. And proteins are colossal. Of course, there is another way to figure all this out: Shining x-rays through a crystallized lump of protein can help reveal the exact position of its folded-up atoms. But that takes time—just 50,000 protein structures have been cracked since the late 1950s, while the sequences of millions of protein-coding genes have been discovered in the past 10 years alone. To make headway in figuring out what all these proteins do, scientists need a faster approach.

Two of Baker’s PhD students, James Thompson and Robert Vernon, groggy from a sleepless night and months of relentless CASP work, finally arrived with the answer. After a brief wrestle with a laptop, they loaded their results. Of the 15 Foldit solutions that Baker submitted to CASP, seven had finished in the money—all of them folded by Poehlman and his teammates. One of their solutions even took first place. A band of gamer nonscientists had beaten the best biochemists.

Arguably, though, the real Foldit victory had come a few months earlier. The creators of the game invited the top players to Seattle, seeking their help in making the app better. Popović contacted Poehlman’s parents. The kid was shocked. ‘Aristides didn’t believe us until we showed him the email,’ his mother says. ‘The silent stare he gave us was priceless.’ Poehlman and his dad, Louis, flew into Seattle late; they played Foldit for hours in their hotel before going to bed—just like at home.

At UW’s computer lab, Popović and his grad students filmed the Poehlmans playing Foldit and interviewed them about their techniques. Louis was exacting in his analysis of how he approached each puzzle, supplying sophisticated justifications for his moves. But when they turned to Cheese and asked him how he knew the way to tweak the proteins—for example, by orienting hydrophobic sidechains toward the protein core—he shrugged and said, ‘It just looks right.’

And that is exactly what Baker was looking for. ‘When I said early on that I hoped Foldit would help me find protein-folding prodigies, it was hopeful speculation,’ he says. ‘It’s fantastic to see it come true.’

The next CASP is two years away, and Baker doesn’t want to lose Foldit’s momentum. He and Popović have given the players a challenge: Design a new protein. Baker’s lab is developing targets for cancer, AIDS, and Alzheimer’s, and the folders’ task is to build a small protein drug with the right shape and binding properties. This isn’t just an intellectual exercise. Baker says he will synthesize the most promising structures and test them in his lab. These proteins could actually have therapeutic value in the real world, outside the game. And if they do, the Foldit players will share the credit. It might be the first time that a computer game’s high score is a Nobel Prize.

John Bohannon (gonzo@aaas.org) is a correspondent for Science based in Vienna, Austria.

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(Via Wired News.)