Hi all, I wanted to share some exciting results we've gotten from folding predictions of Foldit designs!

As many of you know, after a design puzzle closes we submit a selection of Foldit player designs to the Rosetta@home distributed computing project. Rosetta@home distributes your design sequence to 100,000s of home computers all over the world, so that each computer can calculate a prediction about how that amino acid sequence might fold up. This huge dataset of predicted structures tells us a lot about the weaknesses of a design, making this the most rigorous test available to validate designs before we construct the actual proteins in the lab.

The plots below show Rosetta@home datasets from two Foldit monomer design puzzles. Each red dot represents a different predicted structure, and is positioned according to its RMSD (root-mean-square deviation in Cα position; closer to 0 means closer to the designed structure) and its score (a calculated potential energy; more negative score means a more stable structure). What we like to see is a "funnel" running from the upper-right to the lower-left of each plot. This indicates that predictions very different from the design structure are unstable, and that more similar predictions are more stable.

The top-most plot represents the top-scoring solution from Puzzle 798, which we ran in October of 2013. Note that the closest prediction has an RMSD of >2 Å, meaning that no prediction even got close to the designed structure. Furthermore, the closest predictions were not even the best-scoring; the lowest-energy prediction for this structure has an RMSD of 7 Å, representing an entirely different fold.

The lower three plots represent the three top-scoring* solutions to Puzzle 854, which closed a couple weeks ago. Each of these plots shows that the lowest energy prediction is <1 Å RMSD from the designed structure—an incredible result (the first funnel is stronger than many of the designs we come up with in the Baker Lab). Perhaps even more exciting than the quality of these folding funnels is the fact that they were derived from the best-ranked Foldit solutions, whereas in previous puzzles, scientists in the lab have been able to identify poor-ranking designs that fold better than the top-ranked solutions. These are all very exciting results, and a batch of designs from Puzzle 854 is being fast-tracked to lab production presently.

We appreciate all the effort that our Foldit players have invested in adapting to the recent changes in gameplay, and a big thank you especially goes to all those players who have been helping us troubleshoot and fine-tune the latest design tools. Note that we are still working to slim down the client and optimize these tools to be efficient as possible. Likewise, there is still plenty of room for improvement on the side of the Foldit players (we'd love to see some more beta-sheet designs** :P). Stay tuned for results from the lab!

*These are the three top-scoring designs that did not come from the same group, since players from within a group often have very similar top-scoring solutions. These designs are all significantly different from one another.
**We're working on this as well. Foldit is inherently biased towards helices, so this will be a bit of an uphill battle.

( Posted by  bkoep 136 1066  |  Tue, 03/25/2014 - 06:07  |  8 comments )