Online Gamers Solve Protein Structure Mystery
Posted October 14th, 2011
Next time you hear someone complaining about gaming and what a waste of time it is, tell them this story: Players of an online game recently solved a decade-long protein structure mystery.
According to the Center for Game Science, part of the Department of Computer Science and Engineering at the University of Washington, a small group of individuals living on at least three continents, who call themselves The Contenders, solved the structure of a protein that has stumped scientists for more than 10 years. How? From the comfort of their own homes, playing an online protein folding game called Foldit.
The Contenders’ solution and its validation were published in September in Nature Structural and Molecular Biology magazine.
“This is the real deal,” said biophysicist Rhiju Das of Stanford University, who was not involved in the work. “I think [this] really shows how this is a new way of doing science that is more powerful than what a handful of experts could do.”
The protein in question was a retroviral protease of the Mason-Pfizer monkey virus, which causes an AIDS-like disease in monkeys. Over the last decade, many researchers tried various methods to determine the protein’s structure but were unsuccessful. “This viral protein…has really evaded the efforts of expert crystallographers and the very best automated tools,” Das said.
Then one scientist, Mariusz Jaskolski of A. Mickiewicz University in Poland and the Polish Academy of Sciences, turned to an online game called Foldit. Foldit, an extension to the Rosetta@home program, was designed by computer scientists at the Center for Game Science so that home computers around the world could do complex calculations on protein structures. According to UW computation biologist David Baker, while the program ran, users would see a screen saver of the computations. Before long, he began to get emails from users who noticed that the program wasn’t always accurate. They had noticed that the protein, when folding up its helix, was going left when it should have been going right.
Foldit allows users to alter the course of Rosetta calculations, and try to solve protein structures on their own. The goal is to fold up the protein so it has the lowest energy, just as molecules tend to do in real life. Because some Foldit users had demonstrated their potential to solve real protein-folding problems, Jaskolski and Baker decided to put the gamers to the test to see if they could solve the enigma of this particular viral protease.
About 600 players from 41 teams submitted more than 1.25 million solutions. Narrowing those down to 5,000, Jaskolski and colleagues subjected them to a computational technique called molecular replacement (MR), which tests the models against X-ray crystallography data. For MR to work, the proposed structure has to be very close to accurate, in which case the MR calculations can help perfect the details. But previous attempts at MR for this protein had failed because the protein models were too far off the mark.
But The Contenders’ proposed protein structure was a winner. “When we took [their] model, it was a beautiful fit to the X-ray data so we knew [they] had solved it,” Baker said. “We were just totally blown away. This is the first time that a long-standing scientific problem has been solved by Foldit players, or to my knowledge, any scientific gaming participants.”
“It’s kind of an unprecedented case of using computing non-specialists to solve a longstanding scientific problem,” said Alexander Wlodawer, chief of the Macromolecular Crystallography Laboratory at the National Cancer Institute.
The next step might be to provide Foldit users with experimental validation as they play the game, said Das. In this case, the players simply kept tweaking the structure until it produced a low energy score, but they didn’t get any experimental feedback until the very end.
“What if the players do have access to experimental data?” Das asked. “Can they interpret it in the same way that scientists do? Can we turn 10,000 or 100,000 into citizen scientists into real scientists who are developing hypotheses and then doing experiments and then refining their hypotheses?”
If so, Foldit users may not only be able to solve protein structures, but actually refine the rules of the game itself and help scientists reach the ultimate goal of understanding structure directly from a protein’s amino acid sequence.
