In the crossover news of the week, gamers have discovered the structure of a protein-cutting enzyme that plays an important role in the spread of an AIDS-like virus in rhesus monkeys. Knowing the structure of this enzyme – the M-PMV retroviral protease – might make it possible to design drugs to beat the virus, but determining the structure involves first working out how the enzyme’s constituent chains of amino acids are folded. The discovery was made by players of Foldit, an online game developed at the University of Washington that turns protein-folding into a competitive pursuit.
Due to its degrees of freedom, a chain of amino acids can be folded in a staggeringly large number of different ways, making protein folding one of the most difficult problems in molecular biology. Nevertheless, puzzle-savvy gamers produced an accurate model of the structure of the enzyme in 10 days, solving a problem that had been taxing researchers for 10 years.
Software exists to solve these folding puzzles automatically, such as the distributed computing project Rosetta@home, also from the University of Washington, which co-opts idle computers and PS3s for the good of science in much the same way as the better-known SETI@home. But even when brute force is chaperoned by the latest and most sophisticated algorithmic trickery, the combinatorial complexity remains a stumbling block.
As Joachim Pietzsch notes in this background article to a Horizon symposium on protein folding and disease, the molecular biologist Cyrus Levinthal calculated in 1969 that “finding the [final shape] by simple trial and error would be impossible. He said that even if a protein only consisted of 100 amino acids and each of these flexible residues could only take on two different spatial orientations, the protein could theoretically adopt as many as 1030 possible conformations.” This thinking led to what’s become known as Levinthal’s Paradox: generally speaking, a protein attains its structure in milli- or even microseconds, but if it were to arrive at this structure by sequentially sampling the available configurations it would take longer than the age of the universe.
Luckily that kind of thing doesn’t fluster Foldit players. “People have spatial reasoning skills, something computers are not yet good at,” says Seth Cooper, a computer scientist at the University of Washington and lead developer of Foldit, so they tackle the problem in different ways. Spatial reasoning skills plus intuition and collaboration are the heroes of this story: the players who discovered the enzyme’s structure worked as a tag team, sharing works in progress and merging part-correct solutions.
Foldit has been running since 2008. The cracking of the M-PMV retroviral protease is its biggest success to date not only because the enzyme is important in the study of AIDS, cancer and Alzheimer’s, but also because the problem had proved so intractable. “Although much attention has recently been given to the potential of crowdsourcing and game playing, this is the first instance that we are aware of in which online gamers solved a longstanding scientific problem,” notes Firas Khatib, a biochemist at the University of Washington and lead author of a paper on the result (co-authored by the team of Foldit players) published this week in Nature Structural & Molecular Biology.
Crowd-sourcing scientific problems, or “citizen science”, is a growing trend. SETI@home, of course, has been going for 12 years. But Zooniverse now hosts several more recently established projects, including one to decipher ancient papyri and another to detect Kuiper Belt Objects; CERN’s LHC@home gives everyone the chance to help out by running “simulations of beam dynamics and particle collisions”; and then there’s iBat. Surely there are many more. However, Foldit seems unique in the level of intellectual input it demands. If only Sudoko players could be put to good use.
Image: University of Washington via Cosmiclog