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1446: Y1 Receptor Ligand Docking
Status: Closed

Summary

Name: 1446: Y1 Receptor Ligand Docking
Status: Closed
Created: 10/31/2017
Points: 100
Expired: 11/08/2017 - 23:00
Difficulty: Intermediate
Description: This is a follow-on puzzle of Puzzle 1441: Y1 Receptor Homology Modeling. In the previous puzzle, we asked you to model the structure of the human Y1 neuropeptide receptor. In this puzzle, we'd like you to determine how a known binder of Y1 interacts with that model.

We're starting you off with the top scoring structure from puzzle 1441, made by reefyrob and LociOiling. We've placed BIBP-3226 into the homology model, in the approximate location of the binding pocket between the transmembrane helicies. BIBP-3226 is a potent antagonist for Y1, and is speculated to bind in this general location. For this puzzle, we'd like you to find the best location and best interactions of BIBP-3226 to Y1.

As proteins sometimes rearrange slightly around a small molecule, we've allowed for some flexibility in the protein, but as we'd like for you to focus on how the ligand binds, you'll get a penalty if the protein moves too far from the starting model.

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Comments

Susume's picture
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Joined: 10/02/2011
Might try a less optimized pose

Back when foldit used to give us Rosetta predictions to refine, the players complained the starting poses were too stiff in foldit because of being pre-optimized by Rosetta. The devs started giving us a less optimized version of the same shape (not sure if they perturbed them, or pulled them from an earlier point in Rosetta's run, or what). If the solutions to this puzzle show too little variation, you might try giving us an earlier save of reefyrob & Loci's with similar shape, which would be less stiff.

rmoretti's picture
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Looking for ligand variation, not protein variation.

I realize that I could have been clearer in the description, but the primary goal of this puzzle is to move the ligand to find the best location and orientation of the ligand. We're less interested in protein rearrangements, and more interested in the position, orientation, and interactions of the ligand.

To clarify on the background, we know the structure of the ligand and that it binds the protein, but we really don't know exactly where it binds, or how it binds, or the internal conformation it takes when it binds. The ligand was arbitrarily placed in the protein with an arbitrary conformation, and we hope that players can find where it should go.

As the goal of the puzzle was primarily to find the position and orientation of the ligand, and not the internal structure of the protein, providing an optimized protein with structural restrictions was deliberate, so that players could focus on the ligand position, rather than having to re-optimize the protein structure. I did not completely freeze the protein for two reasons. The first is that predicted structures tend to be a little bit inaccurate, and adding a ligand might give additional information which can help correct some of the minor inaccuracies. The second is that proteins sometimes flex and move a little when ligands bind, so even if we had a perfect structure we would need to accommodate that.

Susume's picture
User offline. Last seen 32 min 7 sec ago. Offline
Joined: 10/02/2011
Tips for players

Thanks for the clarification!

Tips on varying the shape of the ligand:

The ligand in this puzzle (unlike other recent ligand puzzles) has "rotamers", which are set positions it can bend into, just like a sidechain has rotamers. With sidechains, the number of possible rotamers changes when the backbone shape changes. With the ligand, I believe the number of possible rotamers will remain constant because it does not have a backbone to change - someone could test this and post results if they want. My ligand and LociOiling's ligand both report 49 rotamers (positions).

The Shake function switches sidechains and the ligand from one rotamer to another if it can find a combination it thinks is better. I believe shake tries to obey rubber bands on the sidechain or ligand if they are present, so you could try banding and then shaking if you have a particular shape in mind. Edit to add: Wiggle All can also bend the ligand, though not as much as switching rotamers can.

To manually switch rotamers, use selection interface, select (highlight) the ligand by clicking on it, and use the left and right arrow keys to step through the rotamers.

Some scripts explicitly cycle sidechains through their rotamers. Those scripts can also change the ligand position IF they operate on the ligand - many foldit scripts are written to ignore ligands, so have a scripter check the one you are thinking of using. Players can help out by posting here names of public scripts that do operate on the ligand and cycle through rotamers.

The lua functions rotamer.GetCount(segnum) and rotamer.SetRotamer(segnum, rotnum) can be used to check how many rotamers there are and to set the ligand (segnum 320) to a particular rotamer. I do not know if a particular rotamer always has the same number - it depends whether the game sorts them somehow as it pulls them out of the database.

LociOiling's picture
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Joined: 12/27/2012
Groups: Beta Folders
rotamer count not changing on ligand segment 320

I created a simple script to flip through all the rotamers for segment 320. So far, the count has remained the same. I'm not sure if the ligand's position relative to the protein could affect the rotamer count, however.

LociOiling's picture
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Joined: 12/27/2012
Groups: Beta Folders
BIBP-3226

Thanks to jeff101 for figuring out that the ligand in this puzzle is BIBP-3226, which was designed for the Y1 receptor.

See wikipedia: https://en.wikipedia.org/wiki/BIBP-3226

In JMol, BIBP-3226 looks like this:

BIBP-3226 seen in JMolBIBP-3226 seen in JMol

In Foldit, it's difficult to get the ligand into exactly the same shape as seen in JMol. Here's a reasonably good effort:



Puzzle 1446 ligand.: The ligand in puzzle 1446 is the designer molecule BIBP-3226.Puzzle 1446 ligand.: The ligand in puzzle 1446 is the designer molecule BIBP-3226.

LociOiling's picture
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Joined: 12/27/2012
Groups: Beta Folders
extra hydrogen - C27H32N5O3 versus C27H31N5O3

For some reason, Foldit shows 67 atoms for ligand segment 320. The formula I get is C27H32N5O3, while BIBP-3226 is C27H31N5O3, at least according to wikipedia.

Looking at the images above, it's not to hard to spot the difference. At the top, there are three blue nitrogens with a gray carbon in the center. JMol has double bond between the first nitrogen and rest of the molecule. Foldit has a single bond and an extra hydrogen instead. Foldit has the double bond is on the next nitrogen, counter-clockwise in this view.

In technical terms, it appears that the Foldit version may be a little goofed-up.

bkoep's picture
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Astute observation!

There is indeed an "extra" hydrogen in the Foldit ligand, but this is not an error.

In water, at physiological pH (close to neutral; pH 7), this ligand will actually pick up an extra hydrogen. The guanidino chemical group (the carbon bonded to three nitrogens in plane) prefers this configuration, even though it means the molecule will have a net charge of +1. You might recognize the guanidino group also from the amino acid arginine (ARG), which behaves similarly—it also has an extra H and a net charge of +1 at physiological pH.

This behavior of the guanidino group is related to its double bond, which is a little bit strange in that it has several resonance forms. The electrons of the double bond are actually shared across all three C-N bonds of the guanidino group. Rather than thinking about the double bond as being between just one C-N pair, as depicted, it's probably better to think about the double bond as being "spread out" across all three C-N bonds. Likewise, the +1 charge is also spread out across the three nitrogen atoms; this is one of the reasons the configuration is so stable.

Susume's picture
User offline. Last seen 32 min 7 sec ago. Offline
Joined: 10/02/2011
Forum thread

There is now a forum thread to discuss scripting ideas for this kind of puzzle.

LociOiling's picture
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Joined: 12/27/2012
Groups: Beta Folders
Atom Explorer

The new recipe Atom Explorer can help to identify the atoms of a ligand or just a regular segment.

All it's really doing is drawing a spaceband to each atom, and recording your input as to what the atom is. Unfortunately, there's no way to tell which atom is which element with just a recipe alone.

The recipe outputs the results of your analysis in table format, which can be imported into another recipe.

For 1446, the table looks like this:

--
--    AtomChart indexes
--    ATCSEG = 1     -- segment
--    ATCATM = 2     -- atom
--    ATCELE = 3     -- element (user pick)
--    ATCBND = 4     -- bonding (user pick, D = donor, A = acceptor, B = both)
--    ATCCOM = 5     -- comment (user input)
--
atomChart = {
    { 320, 1, "C", "", "", },
    { 320, 2, "N", "D", "", },
    { 320, 3, "C", "", "", },
    { 320, 4, "C", "", "", },
    { 320, 5, "C", "", "", },
    { 320, 6, "C", "", "", },
    { 320, 7, "C", "", "", },
    { 320, 8, "C", "", "", },
    { 320, 9, "C", "", "", },
    { 320, 10, "C", "", "", },
    { 320, 11, "C", "", "", },
    { 320, 12, "C", "", "", },
    { 320, 13, "C", "", "", },
    { 320, 14, "C", "", "", },
    { 320, 15, "C", "", "", },
    { 320, 16, "C", "", "", },
    { 320, 17, "O", "A", "", },
    { 320, 18, "C", "", "", },
    { 320, 19, "C", "", "", },
    { 320, 20, "C", "", "", },
    { 320, 21, "N", "D", "OK, not goofy, but BIBP-3226 has double bond to next atom here", },
    { 320, 22, "C", "", "", },
    { 320, 23, "N", "D", "", },
    { 320, 24, "N", "D", "", },
    { 320, 25, "C", "", "", },
    { 320, 26, "O", "A", "", },
    { 320, 27, "N", "D", "", },
    { 320, 28, "C", "", "", },
    { 320, 29, "C", "", "", },
    { 320, 30, "C", "", "", },
    { 320, 31, "C", "", "", },
    { 320, 32, "C", "", "", },
    { 320, 33, "C", "", "", },
    { 320, 34, "C", "", "", },
    { 320, 35, "O", "B", "", },
    { 320, 36, "H", "", "", },
    { 320, 37, "H", "", "", },
    { 320, 38, "H", "", "", },
    { 320, 39, "H", "", "", },
    { 320, 40, "H", "", "", },
    { 320, 41, "H", "", "", },
    { 320, 42, "H", "", "", },
    { 320, 43, "H", "", "", },
    { 320, 44, "H", "", "", },
    { 320, 45, "H", "", "", },
    { 320, 46, "H", "", "", },
    { 320, 47, "H", "", "", },
    { 320, 48, "H", "", "", },
    { 320, 49, "H", "", "", },
    { 320, 50, "H", "", "", },
    { 320, 51, "H", "", "", },
    { 320, 52, "H", "", "", },
    { 320, 53, "H", "", "", },
    { 320, 54, "H", "", "", },
    { 320, 55, "H", "", "bonus hydrogen!!!", },
    { 320, 56, "H", "", "", },
    { 320, 57, "H", "", "", },
    { 320, 58, "H", "", "", },
    { 320, 59, "H", "", "", },
    { 320, 60, "H", "", "", },
    { 320, 61, "H", "", "", },
    { 320, 62, "H", "", "", },
    { 320, 63, "H", "", "", },
    { 320, 64, "H", "", "", },
    { 320, 65, "H", "", "", },
    { 320, 66, "H", "", "", },
    { 320, 67, "H", "", "", },
}

[edit: OK, Foldit view is not goofy, it just looks at those resonances differently]
[edit: missed atom 24, nitrogen donor]

brow42's picture
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Joined: 09/19/2011
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New script to help with ligand

I've created a GUI for banding to atoms: https://fold.it/portal/recipe/102533 . You can use this to help make hbonds, or deform the ligand. It works around built-in restrictions in the regular banding function. You can easily take out the function to use in other scripts, to remake your favorite bands, or random bands.

Susume's picture
User offline. Last seen 32 min 7 sec ago. Offline
Joined: 10/02/2011
Give us another try

I hope you'll give us this puzzle again in a few weeks, now that we know the ligand can change shape and are starting to build tools to make that happen.

LociOiling's picture
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Joined: 12/27/2012
Groups: Beta Folders
paint by numbers

Here are the atom numbers applied to the ligand.

Puzzle 1446 ligand with numbered atoms.: Puzzle 1446, segment 320 atom numbers.Puzzle 1446 ligand with numbered atoms.: Puzzle 1446, segment 320 atom numbers.

Susume's picture
User offline. Last seen 32 min 7 sec ago. Offline
Joined: 10/02/2011
Voids vs bonds

How important is it to get rid of voids around the ligand vs forming bonds? I never play with voids on, and when I checked them near the end of the puzzle I realized I have huge voids even though I have good bonds.

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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, Microsoft, Adobe, RosettaCommons