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2136: KLHDC2 ligand design: Round 1
Status: Closed

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rmoretti's picture
User offline. Last seen 2 hours 44 min ago. Offline
Joined: 01/15/2010
Groups: Foldit Staff
Objective Information

There's a number of objectives. Most of them are there to keep the molecule going "too far" outside the range of acceptable parameters for drugs.

All objectives give +1000 points when fully satisfied, for a maximum of +12 000. Most objectives have a "Show" button which should highlight areas of concern in red. Even when fully satisfied, objectives may highlight groups which may eventually contribute, so it's not recommended to keep Show on at all times.

  • Carboxylate Interaction - A bonus for keeping the hydrogen bonds the existing carboxylate is making. (Show highlights the protein atoms you need to make the hydrogen bonds to.)
  • Ligand Hydrophobic Interaction - A bonus for keeping a hydrophobic interaction between the ligand and the protein. (Show highlights the protein residues the ligand should contact.)
  • Peptide - Penalizes the formation of peptide-backbone-like groups. (Show highlights which parts of the ligand should be changed.)
  • Torsion Quality - Keeps bond rotations in a good range. Using Wiggle or Tweak Ligand can fix bad torsions. (Show highlights torsions to be rotated.)
  • Number of Rotatable Bonds - Intended to keep the ligand from getting too big and floppy. You can reduce rotatable bonds by deleting groups or forming rings. (Show higlights rotatable bonds.)
  • Ligand TPSA - Topological Polar Surface Area - Keeps the polar surface area (including buried polar surface) low. To improve, try removing oxygens and nitrogens. (Show highlights atoms contributing to higher TPSA.)
  • Ligand cLogP - A measure of polarity - Keeps the molecule from getting too hydrophobic. To improve, try adding polar oxygens and nitrogens. (Show highlights atoms contributing to higher cLogP.)
  • Ligand Hydrogen Bond Donors - Keep the number of ligand hbond donors low. (Show highlights atoms contributing to higher cLogP.)
  • Bad Groups - Gives a bonus for avoiding groups that aren't very drug-like, including enol, enamine, thiocarbonyl, hydroxylamines, geminal diols, alpha-beta unsaturated carbonyls, aliphatic alkanes, aliphatic alkenes, aliphatic ethers and others. (Show highlights groups at issue.)
  • Element Counts - Limits certain element numbers: Desired P=0, S<=1, I<=1, Br<=1, Cl<=4, F<=4, N<=5 (Show highlights atoms of elements exceeding count.)
  • Molecular Weight - Intended to keep the ligand from getting too big.
  • Synthetic Accessibility - Identify molecules which are likely to be hard to make in the lab. (Show highlights regions of the molecule contributing to difficult synthesis.)
Joined: 12/27/2012
never break the chain

The protein part of this puzzle has been chopped up into many chains. Some of the chains are only three or four residues (amino acids) long.

The protein in question is PDB 6DO5, titled "KLHDC2 ubiquitin ligase in complex with USP1 C-end degron".

The protein is also known as "Kelch domain-containing protein 2", which is where the KLHDC2 comes from.

The full protein is 363 residues, so cutting it down to 96 residues seems like a good idea. (The full protein also forms a dimer, so there would be two of them to contend with....)

A few Foldit recipes are chain aware, and look at the protein part as chains A through O, with the ligand as chain N. The dialogs for print protein, AA Edit, and SS Edit need a little tweaking to handle 16 chains, unless you have a high resolution monitor in portrait mode. Fixes will be forthcoming.

Joined: 02/01/2022
Groups: Go Science
Bugs

Unfortunately this new puzzle has many bugs. For example adding a C atom killed the program completely. I have to restart it.

Joined: 12/27/2012
#bugs-and-feedback

I'm seeing the same kind of crashes adding an atom or a fragment.

After a crash, if you're on Discord, you can drag the log.txt file from c:\Foldit (or the equivalent spot) over to the #bugs-and-feedback channel. Sometimes log.txt can contain what appears to be useful information. Other times, not so much.

The drag-and-drop trick works if you're using the Discord app. I'm not sure how you do it with the web version, but I assume there's a way.

rmoretti's picture
User offline. Last seen 2 hours 44 min ago. Offline
Joined: 01/15/2010
Groups: Foldit Staff
Fix (hopefully) incoming

From the crash reports, we've identified the likely cause of the crashing, and we have a fix which we think should address it which hopefully should be coming out soon.

rmoretti's picture
User offline. Last seen 2 hours 44 min ago. Offline
Joined: 01/15/2010
Groups: Foldit Staff
Fixes in

The fixes which should address the crashing issues should now be in both main and devprev.

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Developed by: UW Center for Game Science, UW Institute for Protein Design, Northeastern University, Vanderbilt University Meiler Lab, UC Davis
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