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2074: VHL ligand design: Round 5

Closed since over 4 years ago

Intermediate

Summary

Created
November 24, 2021
Expires
Max points
100
Description

Due to issues with objectives, this puzzle has been closed early and is now worth zero competition points. It has been reposted as Puzzle 2074b. All saved solutions from this puzzle can be loaded into the reposted puzzle.



Design a small molecule which can bind VHL! This is the fifth in a series of puzzles using the small molecule design tools to design small molecule binders to the von Hippel-Lindau E3 ubiquitin ligase. We don't want you to modify the protein, but instead we'd like you to build new small molecules which fit into the VHL pocket. See the new "Inside the Pocket" and "Fun with Fragments!" tutorials to learn how to use the small molecule design tools.



Note: To get the most out of the small molecule design tools, we recommend changing you view settings to the Small Molecule Design Preset, or


  • Set Color: Score/Hydro+CPK

  • Set View Protein: Binding Site or Cartoon Ligand

  • Turn on: Show Clashes, Show Voids, Show bonds (non-protein), Show bondable atoms

  • Turn off: Show exposed, Show bonds (sheet), Show bonds (helix), Show bonds (loop), Show bonds (sidechain)




For this round, please focus in on changing the center bit of the molecule. The 'Preserve Structure' objective gives a big bonus if you keep the three-member ring and the linked five and six member rings - leave these end bits alone and change up the bits in between. The 'Alter Core' objective will give a big bonus if you change up the central five-member ring.


Also making an appearance this round are two structural waters. We hope that putting these waters in explicitly will help with maintaining some key interactions to the protein. Also for this purpose is the HBond objective, which identifies the six hydrogen bonding atoms on the protein (and waters) which the starting ligand makes contact to. Their ligand partners can be changed, but another ligand atom should take their place.



This is a project in collaboration with Boehringer Ingelheim. Boehringer Ingelheim has committed to help evaluate and test the molecules which Foldit players have designed. All compounds created as part of the collaboration puzzles will be made publicly available. Experimental results from testing the molecules will also be released publicly. All participants and game sponsors of current and future small molecule design games commit to complying with the Foldit Terms of Service including those pertaining to intellectual property.


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Comments

Aubade01 Lv 1

Structure uploaded for scientists.

It appears to this player that the "Preserve Structure" objective is in error.

Structure does not appear correct.

Aubade00/01

LociOiling Lv 1

The X-ray tunnel for ligand tool is not working on this puzzle in main or devprev. It was working on other puzzles in the series, for example 2062.

Also, wiggle sidechains continues to work via its shortcut "e", but it doesn't have an icon in the new interface action bar. The same issue is true for the selection interface in main, and also on previous VHL puzzles. The "e" shortcut also works in the original interface in main, but there's no menu icon.

rmoretti Staff Lv 1

The issue with the X-ray tunnel might be that it's getting confused due to the two water molecules. I can take a look at things, but it's possibly going to require a code update and/or a puzzle setup change.

Regarding the wiggle sidechains, for this puzzle wiggle sidechains and wiggle backbone were taken out as there's only "sidechain" which can wiggle, so wiggle sidechains is redundant with "regular" wiggle. Not quite sure why the shortcut is still working, but it shouldn't be any harm in running it. (As mentioned, wiggle sidechain and regular wiggle would be identical for this puzzle.)

alcor29 Lv 1

The 'Alter Core' objective will give a big bonus if you change up the central five-member ring. What does "change up" mean?

BootsMcGraw Lv 1

Is no one else going to comment on the 100K top score? Not that I mind my team taking first place on a puzzle. But the puzzle ends in less than forty-eight hours, and it's still valid, when it clearly has a scoring glitch.

I'd rather not waste any more time on this, if the puzzle is going to get canned.

rmoretti Staff Lv 1

We were figuring out the best way to handle this.

We'll be closing this puzzle and reposting it (instead of Round 6). We'll be setting things up such that you can load solutions from this puzzle to the Round 5b puzzle, so hopefully you won't lose any work you've put in so far.