Foldit

bkoep Staff Lv 1

February 10, 2015

Last week the Baker Lab ordered materials to construct the latest batch of Foldit designs in the lab for experimental testing! The following eight protein designs were selected based on visual inspection by our scientists and folding predictions by the Rosetta@home distributed computing project. For each design below, we've included an image of the Foldit player's design on the left; and on the right, a folding funnel with the energy and Cα-RMSD for 100000s of Rosetta@home predictions in red, as well as an image of the lowest-energy prediction. We like to see that the lowest-energy prediction also has a low RMSD (explained here).

For more information about the types of experiments in store for these Foldit player-designed proteins, see our previous blog post.

Monomer Designs
In monomer designs, we were looking particularly for diverse topologies containing some β-sheet secondary structure. Such topologies are significantly more difficult to design than the helical bundles that have been so successful in the past. Consequently, these folding funnels may appear less pristine, but we are still very excited to experiment with them in the lab!

reefyrob retiredmichael Beta Folders, Puzzle 991

Galaxie gmn Anthropic Dreams, Puzzle 995

jamiexq Anthropic Dreams, Puzzle 1029

viosca Anthropic Dreams, Puzzle 1029

Symmetric Oligomer Designs
For designs of symmetric homooligomers, we do a similar analysis to make sure the monomer will fold up as expected.

We also want to make sure that, once folded, the monomer units are likely to bind to each other in the correct orientation. The most common reason a design fails this "docking" test is that its interface is completely hydrophobic and featureless. In such a case, two properly folded monomers can usually come together in a number of different ways to bury the same amount of hydrophobic surface. The best way to ensure specific binding in the correct orientation is to design rugged, complementary surfaces (e.g. large interdigitated side chains) and incorporate hydrogen bond networks at the interface.

The following symmetric designs performed decently for both monomer folding and docking tests (data not shown), and we are excited to try them out—however, we think there is room for improvement in the design of specific interfaces!

johnmitch Puzzle 1018b

gmn MurloW Anthropic Dreams, Puzzle 1027b

TomTaylor Puzzle 1027b

The players responsible for the above designs certainly deserve recognition, but there are many, many more exciting designs that just missed the cut or are still under analysis. We can't wait to see what Foldit players come up with next—keep up the great folding!

jeff101 Lv 1

February 10, 2015

The score vs rms plots in the right column above have red dots and green dots. I take it the red dots are "fold" and the green dots are "relax", but what does that mean? What is the difference between the red and green dots? Are the cartoon structures shown from the red dots region or the green dots region? Are the same cartoon structures shown in the left and right columns, just from different points of view? Thanks!

bkoep Staff Lv 1

February 10, 2015

Yes, the red dots are ab initio fold predictions, meaning that they are produced from scratch, using the protein sequence only (the designed structure is not considered during modeling). The green dots are relaxed structures, in which the designed structure is slightly perturbed and then minimized; this ensures a thorough exploration of the local energy landscape, and provides a score that can be compared with the red ab initio scores.

For each design, the cartoon on the left shows the original structure designed by the player. The cartoon inset in the energy plot is the structure that corresponds to the ab initio prediction with the lowest energy (i.e. the lowest red dot). If the two cartoons are similar, it means Rosetta@home predicts that the provided sequence will actually fold up into the designed structure.

jeff101 Lv 1

February 11, 2015

Thanks, Brian.

Are the rms values for the red and green dots in the plots in the right column how different the structures are from the cartoons in the left column? Does rms=0 mean a red or green dot has the same structure as the original structure designed by the player?

Timo van der Laan Lv 1

February 11, 2015

Please dont use this combination of colours, I am just seeing red dots being RG colorblind. Change the second colour to yellow or blue so I also am able to see both kinds.