Another Success for Foldit: Gamers Increase Enzyme Activity

Another Success for Foldit: Gamers Increase Enzyme Activity by a Factor of 18

Obsessive gamers’ hours at the computer have now topped scientists’ efforts to improve a model enzyme, in what researchers say is the first crowdsourced redesign of a protein.

The online game Foldit, developed by teams led by Zoran Popovic, director of the Center for Game Science, and biochemist David Baker, both at the University of Washington in Seattle, allows players to fiddle at folding proteins on their home computers in search of the best-scoring (lowest-energy) configurations.

The researchers have previously reported successes by Foldit players in folding proteins1, but the latest work moves into the realm of protein design, a more open-ended problem. By posing a series of puzzles to Foldit players and then testing variations on the players’ best designs in the lab, researchers have created an enzyme with more than 18-fold higher activity than the original. The work is published today in Nature Biotechnology2.

“I worked for two years to make these enzymes better and I couldn’t do it,” says Justin Siegel, a post-doctoral researcher working in biophysics in Baker’s group. “Foldit players were able to make a large jump in structural space and I still don’t fully understand how they did it.”

The project has progressed from volunteers donating their computers’ spare processing power for protein-structure research, to actively predicting protein structures, and now to designing new proteins. The game has 240,000 registered players, 2,200 of whom were active last week.

The latest effort involved an enzyme that catalyses one of a family of workhorse reactions in synthetic chemistry called Diels-Alder reactions. Members of this huge family of reactions are used throughout industry to synthesise everything from drugs to pesticides, but enzymes that catalyse Diels-Alder reactions have been elusive. In 2010, Baker and his team reported that they had designed a functional Diels–Alderase computationally from scratch3, but, says Baker, “it wasn’t such a good enzyme”. The binding pocket for the pair of reactants was too open and activity was low. After their attempts to improve the enzyme plateaued, the team turned to Foldit.

In one puzzle, the researchers asked users to remodel one of four amino-acid loops on the enzyme to increase contact with the reactants. In another puzzle, players were asked for a design that would stabilize the new loop. The researchers got back nearly 70,000 designs for the first puzzle and 110,000 for the second, then synthesized a number of test enzymes based on the best designs, ultimately resulting in the final, 18-fold-more-active enzyme.

Science by intuition

“It’s a refreshing twist on enzyme engineering,” says Stefan Lutz, a chemist at Emory University in Atlanta, Georgia, who was not involved in the research. “Using the Foldit players allows the researchers to use human intuition at a scale that is unprecedented.”

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Foldit allows people to explore more drastic changes to the protein than are possible using standard methods such as directed evolution — in which a large pool of randomly mutated enzymes is screened for mutants that improve the original. These mutations are typically just amino-acid substitutions, not the 13-amino-acid addition the players came up with. Systematically testing a change of that size would require testing astronomical numbers of proteins.

“You can explore things that look crazy. When we first saw this particular design we thought it looked crazy,” says Donald Hilvert, a biochemist at the Swiss Federal Institute of Technology in Zurich, who is collaborating with the researchers to further refine the protein through directed evolution.

There are no immediate applications for the particular Diels-Alder reaction that this enzyme catalyses, and, compared with naturally occurring enzymes that catalyze other reactions, it’s not very active. But it marks a milestone in showing what crowdsourcing research can achieve.

Baker is now looking toward more useful targets. The team reported last year that they had designed small protein inhibitors that bind to and block the 1918 pandemic influenza virus4. “Now Foldit players are working to make more potent inhibitors,” Baker said. “Those are exciting because those could be drugs.”

Computational enzyme design holds promise for the production of renewable fuels, drugs and chemicals. De novo enzyme design has generated catalysts for several reactions, but with lower catalytic efficiencies than naturally occurring enzymes1, 2, 3, 4. Here we report the use of game-driven crowdsourcing to enhance the activity of a computationally designed enzyme through the functional remodeling of its structure. Players of the online game Foldit5, 6 were challenged to remodel the backbone of a computationally designed bimolecular Diels-Alderase3 to enable additional interactions with substrates. Several iterations of design and characterization generated a 24-residue helix-turn-helix motif, including a 13-residue insertion, that increased enzyme activity >18-fold. X-ray crystallography showed that the large insertion adopts a helix-turn-helix structure positioned as in the Foldit model. These results demonstrate that human creativity can extend beyond the macroscopic challenges encountered in everyday life to molecular-scale design problems.

This new online game, a protein folding puzzler, is a product of a collaboration between scientists at University of Washington and Howard Hughes Medical Institute. The game is designed to entertain and advance science at the same time. In other words, this is a distributed computing project with built-in fun.

…Howard Hughes Medical Institute (HHMI) researchers at the University of Washington are bringing the arcane world of protein folding to the online gaming arena with the launch of “Foldit,” a free game in which players around the world compete to design proteins. The real world benefit: Scientists will test proteins designed by the game’s players to see if they make viable candidate compounds for new drugs.

Users can access the game via the web at

The development of the online game is a natural extension of HHMI investigator David Baker’s quest to understand how proteins – the building blocks of cells — fold into unique three-dimensional shapes. Over the past decade, Baker and his colleagues have made steady progress in developing computer algorithms to predict how a linear string of amino acids will fold into a given protein’s characteristic shape. A detailed understanding of a protein’s structure can offer scientists a wealth of information — revealing intricacies about the protein’s biological function and suggesting new ideas for drug design.

4532fo2 Solve Puzzles for Science: Fold It!

Predicting the shapes that natural proteins will take is one of the preeminent challenges in biology, and modeling even a small protein requires making trillions of calculations. Over the last three years, volunteers around the globe — now numbering about 200,000— have donated their computer down-time to performing those calculations in a distributed network called Rosetta@home. The computing logic behind the network is an algorithm called Rosetta that uses the Monte Carlo technique to find the best “fit” for all of the parts of a given protein.

Gamers Increase Enzyme Activity

But as the Rosetta volunteers watched their computers blindly trying to work out a solution by methodically testing every possible combination and shape to find the best fit, they began to think that a little human intervention might speed things up. “People were writing in, saying, ‘Hey! The computer is doing silly things! It would be great if we could help guide it,’” remembers Baker, who is based at the University of Washington (UW) where he developed the Rosetta algorithm and network.

Baker didn’t know how he could make that happen until about 18 months ago, when he went hiking on Mt. Rainier with his neighbor David Salesin, a University of Washington computer scientist who also runs a research laboratory at nearby Adobe Systems. Baker and Salesin began discussing ways to make Rosetta more interactive. With the inherent fun of competition, Salesin thought a multiplayer online game was the way to go. By the time they got back to the car, they had settled on that idea. Salesin provided Baker with the names of three colleagues, led by UW computer scientist Zoran Popovic, who could help Baker create the game.

Over the next few months, doctoral student Seth Cooper and postdoctoral researcher Adrien Treuille, working with Popovic and Baker, created the program, and team tested it in small venues. One match between teams from the University of California and the University of Illinois aroused unexpected fervor and cheering among spectators. “30 or 40 people participated,” says Baker. “The competition was very intense.”

“Foldit” takes players through a series of practice levels designed to teach the basics of protein folding, before turning them loose on real proteins from nature. “Our main goal was to make sure that anyone could do it, even if they didn’t know what biochemistry or protein folding was,” says Popovic. At the moment, the game only uses proteins whose three-dimensional structures have been solved by researchers. But, says Popovic, “soon we’ll be introducing puzzles for which we don’t know the solution.”

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