Players of the online protein folding game Foldit have reached another milestone, creating an 18-fold-more-active version of a model enzyme. The gamers worked on an enzyme that catalyses the Diels-Alder reaction, which is used in the synthesis of various chemical products (according to Wikipedia it is considered the “Mona Lisa” of reactions in organic chemistry).
In 2010 scientists designed a functional Diels–Alderase computationally from scratch, but with a binding pocket for the pair of reactants that was too open and too low activity. Because they were not able to improve it further they challenged the Foldit gamers to come up with better designs. Through two different puzzles, one to remodel one of four amino-acid loops on the enzyme to increase contact with the reactants, and another to stabilize the new loop, the gamers fiddled their way through in search of the best-scoring (lowest-energy) configurations. Out of the almost 200,000 resulting designs, the researchers then synthesized a number of test enzymes and ultimately the final, 18-fold-more-active enzyme.
Although there are no immediate applications for the particular Diels-Alder reaction that the enzyme catalyses and its activity is still relatively low, it clearly shows the power of crowdsourcing this kind of research. The scientist are now looking into improving small protein inhibitors that bind to and block the 1918 pandemic influenza virus. “Now Foldit players are working to make more potent inhibitors,” Baker said. “Those are exciting because those could be drugs.”
The work on the Diels–Alderase was published this week in Nature Biotechnology.
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Flashbacks: Solve Puzzles for Science: Fold It!; Foldit Success Story: Monkey Virus Retroviral Protease Structure Solved Within Days