An enzyme designed by players of the protein-folding game Foldit was better than anything scientists could come up with.
Image: Foldit
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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 proteins, 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 was published January 22 in Nature Biotechnology.
"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 synthesize everything from drugs to pesticides, but enzymes that catalyze 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."
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.
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9 Comments
Add CommentHow many crowdsourced gamers will we need to figure out how to make the Israelis and Arabs live in peace?
Reply | Report Abuse | Link to thisI can't see why someone couldn't at least try it.It is only a game after all and if no solution is presented then no harm done,but if a solution is achieved then wow.
Reply | Report Abuse | Link to thisWhile Foldit is at it why don't the Foldit group ask the gamers to improve the Haber process ?? I am thinking the concept can be applied to non biological problems.
The reference to directed evolution recalls evolutionary algorithms and genetic programming, where for example populations of computer programs can be made to
Reply | Report Abuse | Link to thisevolve ways (via 'mutation, crossovers, selection etc.') to create solutions to problems (eg: in electrical engineering).
The Foldit project seems to qualify as an example of
James Surowiecki's book "The Wisdom of Crowds" and his criteria for best decision making by crowds/groups
1) Diversity of opinion
2) Independence
3) Decentralization
4) Method of Aggregation of Results
Ie: Bad decision making by large groups involved the
lack of one or more of the above four conditions.
A short Wikipedia entry is at:
http://en.wikipedia.org/wiki/The_wisdom_of_crowds
It struck me that in a very loose way, these criteria also define some of the conditions prevailing in the biological world for the evolution of new species
of organisms. Ie: Populations undergoing selection-forces contain a vast diversity of genetic information and undergo independent mutations and cross-over
events...etc.
Does anybody know of a formal connection between the two phenomena?
No, but I see what you mean.
Reply | Report Abuse | Link to this@Polynumeral
Reply | Report Abuse | Link to this"I am thinking the concept can be applied to non biological problems."
Absolutely. Newsvine typically seeds public opinion with political issues, then collects public opinion and datamines it for emergent structure. What is crowdsourcing but that?
Can we use crowd sourcing to change political thinking. For instance the geographic boundaries of nation states was dictated by geographic barries. Today it is defined by special interests - immigration.
Reply | Report Abuse | Link to thisAn individual is NOT free to travel and should be free to as long as he/she has not violated the laws of the nations he/she belongs to and the nation he/she wants to visit.
Can we try such ideas and change the systems in wild West?
Crowd sourcing is an amazing tool for science. Congratulation to the FoldIt team and players! There's a lot of potential to using the crowds and clouds -- to explore the geo-temporal tagging, I've set the CrowdMappers LinkedIn group. Those that are interested, I hope you join our discussions -- I'm posting the link to this article to our group. Thanks!
Reply | Report Abuse | Link to thisFoldIt works because the system whereby FoldIt progresses has a fundamental structure within which the players have a great deal of flexibility. Crowdsourcing frequently fails when the decision making is left unstructured. When I have a cola company the last thing I want from my crowdsourcing effort is the result of "orange juice".
Reply | Report Abuse | Link to thisThe crowdsourcing has to have that fundamental set of rules that prohibits completely undesirable results. After all, a riot is also a result of crowdsourcing.
As GM found out when they crowdsourced the Electric Car. To bad they and the oil companies make too much money on the gas powered ones, but if your CS effort resulted in "OJ" wouldn't you shift at least some effort to producing it?? (Unless it cut into your cola sales)
Reply | Report Abuse | Link to thisYou don't need to set rules, just weigh all the outcomes, besides... who is going to decide "undesirable"? After all, the Christmas Truce was a result of crowdsourcing. (But VERY undesirable to those trying to wage war, and also to those making a profit off outfitting the troops, selling tanks, bullets, etc.)
@atomikrabbit - you just need to design the game! I think the movie "Wargames" might be a good start.