10 replies [Last post]
Susume's picture
User offline. Last seen 6 hours 16 min ago. Offline
Joined: 10/02/2011

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3070793/figure/F2/

If you look at this illustration, you can see that the blue protein's sheet is not flat but has a fan shape, with each strand turned a little clockwise from its neighbor as you move from background to foreground. The helices, following the fan of the sheet, are not parallel but slightly skew. I think of this fan shape as the natural shape for sheets, and in the recent denovo puzzles I have carefully set up my sheets in a fan shape, and skewed my helices to match. Then I run enhanced DRW for a really long time, and the foldit score function gradually flattens my sheets and parallelizes my helices. Every time. The same happens in design puzzles - I set up fanned sheets, and the score function does its best to flatten them.

The foldit program can't "see" the fan shape, only the subscores of the individual amino acids. Somehow optimizing those subscores creates a less natural overall shape. As a human I can see the shape I want to create, but the program is working against me. Why is that? Could the score function be tweaked to allow sheets to remain fan shaped?

A related question was raised by spvincent prior to the last science chat but did not get covered: http://fold.it/portal/node/2001726#comment-31713 Sometimes you get parallel structures in design puzzles because humans like things straight and tidy. But other times the humans create curved or fanned or skewed structures, and foldit straightens them anyway.

jeff101's picture
User offline. Last seen 7 hours 19 min ago. Offline
Joined: 04/20/2012
Groups: Go Science
Use bands to preserve the fan?

Perhaps using bands on the fan shape will preserve it long enough for it to stabilize.
Then you can remove the bands and it will stay in place.

Recipes like the following at first glance sound useful for this:
Zero Length Bands v 2.0.1 -- Brow42 (http://fold.it/portal/recipe/37147)
CG303 Scaffolding Helices V2.50 (http://fold.it/portal/recipe/41821)
Scaffolding sheets V1.1 (http://fold.it/portal/recipe/9448)
Scaffolding V1.1 (http://fold.it/portal/recipe/8710)
The Hedgehog 1.1 (http://fold.it/portal/recipe/101696)

Skippysk8s's picture
User offline. Last seen 17 hours ago. Offline
Joined: 06/06/2013
Groups: Gargleblasters
thanks for comments -- re Jeff's question about 0 bands

Jeff, I have stubbornly persisted a few times in holding a shape with bands. I usually do better to do it for a day at most ( I have a slow computer) and then let things go. I get better results, though nothing as good as Susume yet. But I keep trying :)

brow42's picture
User offline. Last seen 3 days 3 hours ago. Offline
Joined: 09/19/2011
Groups: None
Related, Rosetta@Home

A related observation: Rosetta@Home decoys are given to us with crazy (but optimized) sheets, cis peptide bonds, beta bulges...all things Foldit hates and quickly eliminates. Creating these on purpose is almost impossible, but common in the decoys. Why is that? I suppose that's the difference between 100 folders and 100,000 folders, maybe.

bkoep's picture
User offline. Last seen 1 day 4 hours ago. Offline
Joined: 11/15/2012
Groups: None
Interesting question

Thanks for bringing this up, Susume!

You're right that beta sheets tend to have some twist (slightly differently, I think, between parallel and anti-parallel arrangements), which arises from the geometry of the protein backbone. A "flattened" beta sheet is generally a little more strained, although this can be offset by other favorable interactions (e.g. sidechain H-bonds, packing, etc.).

In any case, I'm a little bit surprised that Foldit is hostile to twisted beta sheets—I can't think of any reason that the energy function would favor flat sheets over twisted sheets. My best guess is that this is a secondhand effect of the DRW script. Do you see this phenomenon with other scripts as well?

The Rebuild tool itself has some serious shortcomings, and I have a hunch that Rebuild is responsible for a lot of backbone issues we see in Foldit structures. We'd like to do an overhaul of the Rebuild tool, and this is high on our to-do list.

Susume's picture
User offline. Last seen 6 hours 16 min ago. Offline
Joined: 10/02/2011
Maybe the bands

I am beginning to suspect that some of the flattening may be due to my habit of leaving weak bands on the sheets during DRW (they are enabled during wiggle but disabled during rebuild). I have begun experimenting with banding the sheets in space (great suggestion from jeff101) or only banding the middles of the sheets, and I see less flattening (although still some, I think). I'll keep trying that for a while and see how it goes. I don't know if other scripts also flatten things; I'll try changing my script order on a few denovos and see what happens. DRW is always the first script I run for any length of time, and it changes the shape more than the other scripts I run (and also gives me the majority of my points on each protein, so you would expect it to make the most change).

Susume's picture
User offline. Last seen 6 hours 16 min ago. Offline
Joined: 10/02/2011
Rama map helping

Having loops built according to the Rama map on 1208 has resulted in a nicely curved sheet!

spvincent's picture
User offline. Last seen 8 hours 16 min ago. Offline
Joined: 12/07/2007
Groups: Contenders
I wonder if a contributory

I wonder if a contributory factor to the flattening might be the length of the loop joining two strands of an anti-parallel sheet, assuming that's the form the sheet takes. It's easy to imagine that with, say, a tight 2-segment loop between strands the overall structure might be quite constrained and unable to stay in the preferred position, whereas something like a 4-segment loop might confer a lot more flexibility.

brow42's picture
User offline. Last seen 3 days 3 hours ago. Offline
Joined: 09/19/2011
Groups: None
Science Questin: Sheet design puzzle

We recently had a design puzzle that preferred sheets. Some players made a sheet sandwich and some made beta barrel. We all made hydrophobic cores. But what structural component in real proteins lead to one or the other?

bkoep's picture
User offline. Last seen 1 day 4 hours ago. Offline
Joined: 11/15/2012
Groups: None
Good question

I'm not the expert on this, but I can tell you what I do know. Perhaps I can track down another Baker lab scientist to follow up...

In many beta barrels, there are key positions that adopt irregular backbone conformations to reshape the beta sheet. Some positions adopt a "beta bulge," in which an extra residue is inserted between two residues of a beta strand. In the primary sequence, this residue would interrupt the normal pattern of alternating polar and nonpolar residues. There are also "glycine kink" positions, in which a glycine residue deforms the beta sheet by adopting a conformation unfavorable for other amino acids.

In beta sandwich proteins (and in many other structures with beta sheets), the "edge strands" of a beta sheet are often sprinkled with polar residues on the core-facing side of the sheet (which is normally nonpolar). Sometimes these are residues like TYR, which has a hydrophobic region that can contribute to core packing, as well as a polar atom that can extend out into solvent to make hydrogen bonds.

Susume's picture
User offline. Last seen 6 hours 16 min ago. Offline
Joined: 10/02/2011
Improved Ideal SS

The Oct 6, 2016 release has an improved Ideal SS tool that starts sheets out with more twist than they used to have - it remains to be seen whether they will keep their twist throughout the folding process.

Comments on that release: https://fold.it/portal/node/2002921

Sitemap

Developed by: UW Center for Game Science, UW Institute for Protein Design, Northeastern University, Vanderbilt University Meiler Lab, UC Davis
Supported by: DARPA, NSF, NIH, HHMI, Microsoft, Adobe, RosettaCommons