Nature Medicine | Spoonful of Medicine

FoldIt game’s next play: crowdsourcing better drug design

Two years ago, FoldIt made headlines, lots of them, when players of the online protein-folding video game took three weeks to solve the three dimensional structure of a simian retroviral protein that is used in animal models of HIV, but whose structure had eluded biochemists for more than a decade. Seth Cooper, the game’s co-creator, captured the attention of the crowd at the TEDMED medical technology conference in Washington, DC by recounting how thousands of players competed in that FoldIt challenge despite the lack of prize money or prestige. He even brought on-stage the winner, a beaming British lab technician named Mimi Minet whose identity had not been previously disclosed to the public.

But the hidden news, the ‘Easter egg’, so to speak, was that Cooper and his collaborators are updating FoldIt to leverage the power of online gaming to create new proteins—enzymes that could form the basis of novel drugs or improve how they are manufactured. This freshly expanded enzyme design platform for FoldIt saw initial success in January, when gamers using an early version created a blueprint for an enzyme that lab tests indicate speeds up a type of biosynthetic reaction used in the production of a variety of drugs—including the cholesterol medication lovastatin—by almost 2,000%.


Designing small molecules, which are not composed amino acid chains as proteins are, but still function according to their 3D folded shape, requires that Cooper and his team in Seattle add to the chemical building blocks available to FoldIt players. “To build proteins, players can swap out amino acids in a protein,” he explains, “and there are only 26 amino acids, so compiling the building blocks players will need is easy.”

For example, players can swap a tryptophan for a cysteine in the active site of a potential flu inhibitor and see how it changes the protein’s stability and its interaction with target proteins on the surface of the flu virus. But in order to design small molecules, FoldIt will need a new toolbox of organic subcomponents such as rings and chains of carbon that players can then piece together into larger molecules, adding functional groups like alcohols or sulfurs to create novel small molecule chemicals. Since there the number of organic subcomponents is virtually infinite, creating such a library is daunting, but “we’re hopeful that we’ll have a small molecule in the next year,” says Cooper.


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    Jennifer Cable said:

    This is so very cool! I’ve always thought that rational enzyme design and structure-based drug design were lagging behind their full potential. Hopefully now, with so many people on board, some really great advances will be made. And, this is a great way to teach students about protein structure, drug design… I taught a class of sixth graders an after-school course on structure-based drug design. We used a chem drawing software to draw a small molecule drug and a Pymol plug-in to dock it onto our protein and get binding energies, not sure how robust it was, but a great learning experience. This sounds like it would be even better, having every step in one place.

    I’m excited to try it out!