Closed since over 8 years ago
Intermediate Small Molecule Design PilotThis is the first official small molecule design puzzle. The goal is to change the ligand in the center of the protein to find better inhibitors of HIV protease. Use the Ligand Design tool in the selection interface (or the "Ligand Design" mode in the original interface) to alter the chemical identity of the inhibitor. See the blog post for more information on the puzzle and small molecule design.
As recommended in one of the blog posts, it's easier to use selection mode. Also, the "Cartoon Ligand" view option and "Ligand Specific" coloring option may help.
In selection mode, you can select the ligand, segment 199. (Ligand-specific coloring makes it stand out.) The ligand tools then appear along the bottom of the window.
The "Design Ligand" option, or shortcut L, initially has all its sub-options greyed out. Click on one of the atoms of the ligand to select it. The selected atom is highlighted with a halo, and the valid options are no longer greyed out.
The exact options depend on the atom. If your atom is eligible for one of the larger molecules (CO2 through benzene), hovering over the option gives you a preview of what things would look like. (Hint: carbon has more options.) No previews for simple atoms, however.
The other options seem to do something as well, and so far no crashes. The Ligand Queue tool is a bit confusing, and it's not clear what MMFF Wiggle does, but it's good for losing points.
It can be a little hard to tell which atom you've selected. The CPK colors are changed due to having the whole ligand selected. Otherwise, nitrogen is blue, oxygen is red, sulfur is yellow, hydrogen is white, and anything else is carbon. The Small Molecule Color under Ligand Properties lets you change the carbons to yellow if you want, but it's a slightly brighter yellow than sulfur's yellow.
Atom selections are cumulative, so when you click a second atom, the first stays selected. You can click the first atom again to deselect it.
It's easy to deselect the ligand if you click in the wrong spot.
Atom choices aren't always valid, even when they're not greyed out. If you make a bad pick, the error message tends to hide behind the options. (Moving the ligand up the screen may help.)
Aside from that, it's just a simple matter of biochemistry….
Keep in mind that it's still early days with the small molecule design puzzles. We're still working out how best to enable the effective design of small molecules in Foldit.
1) We're still working on the intro puzzles for the small molecule design features. If you have suggestions on how to approach making an effective intro puzzle for these tools, please let us know.
2) If you're referring to the Ligand View tools, none of those are going to change the structure (and hence your score) - they're purely for getting more information out of the structure. You hopefully will be able to use that information to inform your design strategy, and to inform which modifications you make.
5) If you're referring to recipe scripting, the Ligand Design functionalities aren't necessarily exposed yet. One complication is that the Ligand Design tools work on an atom-by-atom basis, versus other tools in Foldit, which work on a residue/segment-level basis. How to effectively work selecting particular atoms into the recipe scripting system is an open question. – If there are any recipe writers out there who have ideas, please let us know.
3 & 6) The main activity which you'll be performing during a small molecule design puzzle is using the Ligand Design tools to change the chemical identity (how the bonds and atoms are connected) of the central ligand to make new and better scoring ligands. You'll probably also want to use the other Foldit tools like shake and wiggle to optimize the ligand into the structure and the structure around the ligand. A successful small molecule designer will likely use all the tools at their disposal to optimize the structure.
4 & 6) As a new puzzle type, the best strategies for approaching these puzzles are something you (as part of the Foldit player community) have to figure out. I can't necessarily say what approaches are going to work out - that's as much a mystery to me as it is to you. Like the early days of protein folding, where Foldit strategies needed to be developed, the precise approach one should take on small molecule design puzzles is something to be worked out.
That said, all the principles from protein folding should also apply here. Hydrophobic (carbon/hydrogen rich) sections of the ligand should be buried with hydrophobic sidechains. Polar (oxygen/nitrogen righ) sections of the ligand should either be exposed or (preferably) be making hydrogen bonds to the sidechains and backbone of the protein. Polar sidechains in the ligand binding side should be paired up with polar groups on the ligand, such that they make hydrogen bonds. Good packing of the ligand/protein interface is also important, so fill voids without making clashes. (Also keep in mind that the protein also contributes to the score, so don't make the protein unhappy to better fit the ligand.) The wrinkle for ligand design versus standard protein design is that you have relatively free rein to change the identity of the ligand to accomplish this.
As I said, it's still early days, and it's going to be a learning experience for both sides. I completely anticipate that we (as developers) will learn things from these early small molecule design puzzles which will change how we set up these puzzles, to make it easier for players to achieve success. (This is similar to the protein design puzzles, where there's been multiple iterations of puzzle settings, and new tools introduced to help with that process.)
I'd love to see an import SMILES function added
Thank you for the explanations, I am making progress now.
Shake seems to produce a stop on the undo graph for every sidechain that moves, rather than one stop for the entire shake. I shook for over 3 minutes, and the iteration counter still said 1 but there were 28 blue stops produced on the undo graph.
"Ligand is very unlikely unsynthesizable." Total UNs in this sentence: 2 is too high!
When trying to select or deselect a ligand atom, if there is another atom immediately behind the one I am clicking, the game consistently highlights (or de-highlights) the one behind instead of the one in front. When I turn the view so there is no atom behind my target and then click in the same way, it highlights/de-highlights the one I want.
Is there a numbering scheme for the heavy atoms that would remain consistent as we add and remove atoms? It's very hard to keep notes or remember what you tried when you can't identify an atom as the same one you changed last time.
