New Foldit tool: Pick Sidechains

We're introducing a new Foldit tool for folding protein side chains, called Pick Sidechains. Pick Sidechains is currently available to devprev users for testing, and soon will be released for all users!

To use Pick Sidechains, select a segment of your protein and click on the Pick Sidechains button. This starts the tool, which runs continuously until you stop it with the Stop button in the upper left corner of the screen (just like Shake, or Remix).

Pick Sidechains displays a cloud of all possible side chain positions for the selected segment. Each possibility is called a rotamer. Use the mouse to hover over the cloud and highlight individual rotamers. Left-click on a rotamer to apply it and see how it affects the score of your solution.

When you start Pick Sidechains, a new panel will appear that shows the segment you selected, along with a list of rotamer options for that segment.

Every rotamer in the list is labeled with a shorthand name, using the letters ‘m’, ‘p’, and ’t’ to describe the rotation of each bond in the side chain (for “minus”: -60º, “plus": 60º, or “trans": 180º).

The panel also includes a gauge for each rotamer’s prevalence. Certain rotamers are more common than others, and these are typically preferred for protein folding. A full gauge indicates a common rotamer, while a rare rotamer will have an empty gauge. More common rotamers will usually score better, but sometimes a rare rotamer can make an excellent hydrogen bond or fill a void to gain more points!

After you have picked a rotamer, stop Pick Sidechains with the Stop button in the upper left corner of the screen.


A tool for H-bond Networks

In most cases, the Shake tool will still be the fastest and most effective way to fold the side chains of your protein. Pick Sidechains is meant for special situations where Shake performs poorly. One example is designing H-bond Networks.

Shake is not very good for designing H-bond Networks, because it doesn’t know about puzzle Objectives—Shake can only optimize the base Foldit score (without Objective bonuses). This means Shake will sometimes ignore a potential H-bond Network because other rotamers improve the base score, even if the network would yield a huge Objective bonus for more points overall.

In these situations, it’s up to Foldit players to design H-bond Networks by hand. Pick Sidechains should give players improved manual control over side chains, and hopefully will help players design better H-bond Networks!

An example of a well-satisfied H-bond Network designed by fiendish_ghoul in Puzzle 1561. This network spans the interface between the two symmetric units, and is located in the core of the protein, with nine polar atoms that need to form hydrogen bonds (numbered 1-9). Since these atoms are buried in the protein core and cannot make H-bonds with the water around the protein, they need to form H-bonds with each other. Note that there are un-bonded hydrogens on atoms 3 and 5, so this network is not completely satisfied—still, this network is over 80% satisfied, which is very impressive! The Shake tool is unlikely to find well-satisfied H-bond Networks on its own, and may require guidance from Foldit players. Pick Sidechains can help Foldit players build H-bond Networks.


Tips for using the Pick Sidechains

You can select more than one segment for Pick Sidechains, to view multiple rotamer clouds at once.

Some side chains (ASN, GLN, HIS, THR) have different atoms with different bonding abilities, but it can be hard to tell these atoms apart in the default Foldit view. If you have enabled "Show advanced GUI" in General Options, then you can change your View Options to one of the “CPK" Colors (like "Score/Hydro+CPK”). This will color oxygen atoms red and nitrogen atoms blue.

Some side chains (CYS, SER, THR, TYR) have a hydrogen that can be rotated to form hydrogen bonds in different directions. However, this hydrogen is hidden by default. In the View Options menu, change the View Hydrogens setting to “Show bondable hydrogens” to see these hydrogens in your protein. If hydrogens are visible, then Pick Sidechains will display extra rotamers so you can control the position of the hydrogen.

( Posted by  bkoep 80 632  |  Mon, 12/03/2018 - 19:49  |  5 comments )
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S0ckrates's picture
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I've been waiting for this!

I haven't even playtested this yet, but already my first impressions of it is that it looks absolutely GOLDEN for sidechain manipulation. No more finicky sidechain pulling or using the arrow keys for rotamer shuffling that makes the game run at the framerate of a PowerPoint presentation! Just point, click, and be done with it. This'll be great not just for H-bonding puzzles but I bet future electron density puzzles will be much better with this. Plus I think the rarity gauge is really useful information; I'd like to think as a player I'd love to use a conformation that fits the bill but doesn't bend over backwards to achieve what I need.

Off the bat I could think of a couple Q.o.L. bells and whistles to enhance the end user experience: Having the top of the rotamer list furnished with labels/sorting buttons could make it a little more clearer. Something like "Bonding Angles | Rarity" with options to sort by ascending or descending rarity or alphabetical sequence of angles.

I might just duck my head into devprev for this on stream this Friday, if it's patched in.

Lastly, one question: Does this have to be used in Selection mode? Or will a shortcut be located in the pie menu if I right click on any given sidechain?

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.

This is available in the Original interface pie menu as well, but the Selection interface gives some additional functionality in that you can select multiple residues and explore their sidechains in combination.

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Playtest update

After playing with this it's a very strong tool. Some end-user notes:

- When using it in symmetric dimer design, since it acts like Tweak/Remix, it can be a little annoying having to click/cycle hotkeys to mutate sidechains after figuring out that the sidechain I was trying wasn't going to work out.
- When playing Electron Density, I realized that I very much would like the Quality of Life change of having the rotamers sortable or filterable by rarity and sequence of identifiers. I would come across times where I would think "Okay, I need 'mt' followed by something for this arginine" but I'd need to sift through all the rotamers on the list since all the mt--'s weren't clumped together.
- When playing Electron Density, my playstyle involves snipping off individual residues, positioning them using the move tool, then (now that it's in) using Pick Sidechains to pick the appropriate rotamer to match the cloud. As with the Sym. Dim. Des. puzzles, it is a little annoying to go in and out of the tool mode to reposition or rotate the residue then bring up the ghost sidechains again to see if they align properly. Very useful though, with longer or branched ones I find it easier to use the mouse-over list, but for the aromatic residues I usually rely on the visual ghost sidechains more for selection projection
- Selection Interface usage is quite useful indeed, the mutation delay mentioned before is still applicable. Makes me wish for a Selection Interface toggle hotkey though.

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This will never make me as good as Fiendish....

But thanks. Looks good. Next stop is getting dimers to bond...lol

Away or busy most of this week, so looks like I can have fun next week

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Minor edit

This tool was originally released as "the Sidechain Picker." It has been rebranded "Pick Sidechains," which is more in line with the names of other Foldit tools.

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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, Amazon, Microsoft, Adobe, RosettaCommons