Closed since almost 2 years ago
Intermediate Overall Small Molecule DesignUse the Ligand Queue (default hotkey 7) to explore how different ligand bind to the protein.
This puzzle is part of the CASP16 competition. Foldit players are participating to see how well they can predict how small molecules can bind to proteins. Note that in contrast to prior drug design puzzles, we're not just interested in the top scoring small molecule, but instead are interested in getting good structures for each of the provided ligand compounds. Its worth dividing your time across all the compounds, rather than concentrating on a particular one.
The protein target is the Human Chymase protease There are a number of structures of chymase bound to ligands at the PDB. There are 17 ligand structures of interest in this competition. The starting small molecule is from a known crystal structure, and is provided just to indicate the likely binding site. It's not one of the molecules in the competition - you'll need to use the Ligand Queue tool in order to load one of the other ligands.
Since the goal is to predict the structure of the protein ligand complex, we've allowed full backbone and sidechain flexibility on this puzzle. -- That said, all of the bound structures are highly similar to each other (and thus to the starting structure). The backbone is very unlikely to change at all from the starting conformation.
@BootsMcGraw But if my modified small molecule scores better than its original form, wouldn't it be a better candidate as a ligand than the original?
Quite possibly. However in CASP (in contrast to CACHE), there's no compound synthesis or testing. The compounds for which there's experimental data are pre-determined before the competition began. Only those compounds are relevant for the puzzle.
@HuubR I was somewhat surprised to find that it is still possible to use the Small Molecule Design panel.
I'm surprised as well. I thought we fixed that bug. But apparently it's just fixed for switching puzzles while the client is open, not close-the-client and reopen. – Thanks for the reproducibility case. We'll take a look at it.
which, by the way, doesn't have a puzzle number
Oops. That should be corrected now. Thanks.
Assuming that there will be a next round to this puzzle, would it be an idea to include a bonus for using one of the 17 ligands (like the +4000 point Compound Library objective in Puzzles 2363 and 2366), but with a different value for each of those 17 ligands?
I think this could solve two problems:
With this bonus, it would also be possible to simply enable the Small Molecule Design tool. I think it would help if we can use it, because some of the ligands only differ from each other by one or two atoms, and it is much easier to make that change with the tool than it is to use the Ligand Queue and then have to re-align and Tweak the new ligand.
I thought I might be the only one doing it this way, but @nspc just mentioned in Discord that he prefers to work this way, too.
If there will be a follow-up puzzle to Puzzle 2452 with the same protein and same ligands, please let it load our results from Puzzle 2452. I know many of the results I have obtained so far in Puzzle 2452 could be improved with more time.
if you want to ensure full attention to each ligand just create separate puzzles. if you have one ligand that scores well, it breaks the comparison scale: you can't compare how well your current lower-scoring ligand is scoring in regard to your other lower-scoring ligands, but worse, you can't compare it to other players' as well and that's game-breaking for me. if the final point is just having a rough idea of where the binding site is, you can even lower the duration of those puzzles (i could go for one day but two or three may be more consensual)
