355: CASP is over... BOOM! TNT Design Puzzle

Closed since over 15 years ago

Summary

• Created: August 19, 2010
• Expires: August 27, 2010 at 23:00 UTC
• Max points: 100

Description

Is that...?! Yes, it is! It's TNT! We've got a very energetic, high profile molecule for you guys to bind. Sure, we already have antibodies that bind TNT, but they're very expensive to make. Wouldn't it be better if we just designed an easy to express protein that bound TNT? We could use it to make cheap detectors and sensors so we can look for TNT contamination or explosives! Brilliant! Remember, there is more than one way to play these design puzzles since we look at all the designs and the best scoring design may not necessarily be the most useful/promising. Check out the puzzle comments for hints!

Top groups

• 1. Contenders 100 pts. 11,079
• 2. Anthropic Dreams 84 pts. 11,063
• 3. Void Crushers 70 pts. 11,035
• 4. Mojo Risin' 57 pts. 11,028
• 5. Russian team 47 pts. 11,015
• 6. SETI.Germany 38 pts. 11,010
• 7. Richard Dawkins Foundation 30 pts. 11,009
• 8. Go Science 24 pts. 11,009
• 9. Deleted group pts. 11,006
• 10. Deleted group pts. 11,000

Top soloists

• 1. Bletchley Park 100 pts. 11,079
• 2. CharlieFortsConscience 99 pts. 11,071
• 3. marie_s 98 pts. 11,056
• 4. Mark- 97 pts. 11,044
• 5. mat747 96 pts. 11,035
• 6. jakyl 95 pts. 11,033
• 7. TheGUmmer 94 pts. 11,030
• 8. steveB 93 pts. 11,029
• 9. sandir 92 pts. 11,028
• 10. chansuke 91 pts. 11,026

Comments

[saksoft2]

I appreciate the complexity to what we do in Foldit. And I understand the nuanced complexity of shell modification. Also, I admit that I am just a newbie compared to many of you in the Foldit community. However, I am not sure that Foldit has the tools we need to do this kind of binding design.

A: The full ligand is not available, only the active tail of it. Maybe the designers could have included a few more segments of tail to give us a better image of what the biotinized model would be?

B: The scoring system, by which many people are judging the "worth" of their modifications is based on optimizing the design protein and not necessarily the matching space to the ligand. The way I understand the criteria:

i: must bind to ligand
ii: must stay open enough to allow the ligand to reach the binding sites
iii: design for minimal protein energy that meets criterias i) and ii)

Maybe what I am really wishing for are the additional scores of "accessibility to the binding site" and "ligand compatibility"?

C: What types of changes are the designers looking for in the design protein once it binds with the target ligand? What I mean is that the normal shape (best energy score) of the design protein will be the one without the ligand present so it only makes sense that any binding to the ligand will alter that configuration in some way. How much of a difference should there be once the ligand is added to the mix? Should the "score" raise, lower, or stay the same? How does Foldit adjust the total score with the protein-ligand bonding in play?

As I said above: I am still very much a noob to folding and using Foldit, so please take my questions with a grain of salt.

[austinday]

@infjamc: Right on. The reason we hold the backbone locked and restrict the residues you can mutate is because the more we modify a protein, the less chance we have of it actually folding into that predicted structure. Additionally, we have found that doing design while keeping the backbone locked also yields a better chance. (Backbone movement is a REALLY hard thing to predict accurately.).

@saksoft2: A) I'll see if I can put up a pdb or an image of the full ligand we are trying to bind.

B) In the puzzle, the score contributions that the ligand participates in are upweighted relative to the rest of the protein (I believe I made this puzzle such that the interactions with the ligand are worth 2X). I totally understand the desire for a better scoring function for certain aspects. There are definitely things we can add, like a shape complementarity measure or a local measure of solvent accessible surface area (to perhaps get an idea of how solvated the last atom in the tail is?) I'm not a great programmer though, so I can only pass on these suggestions to the masters and hope there aren't too many other programming priorities ahead of mine. Although I'm sure if we get enough complaints/suggestions from players, that might get some attention. :)

C) I believe that the ligand score is basically the score difference between the score when the ligand isn't there and the score when the ligand is there. Due to the upweighting, the optimal score should be with the ligand present.

There are examples of proteins that don't really change their conformation much at all when they bind their target (antibodies), and there are examples of proteins that change around quite a bit upon binding (periplasmic binding proteins, streptavidin) so we don't think that it is necessary that we design in a movement that occurs upon binding. (it might be sufficient to try and design the perfect shape that doesn't move regardless of the presence of the ligand) That's kind of the strategy we are going for right now (since it's way too inaccurate to try and design in a backbone movement right now). That's kind of the idea behind that last "hint" I gave. (The one where it would be good to see that the residues that interact with the ligand stay in those positions even when you remove the ligand and repack.)

I think I might have answered a different question above, so I'll try again with possibility #2. In terms of the total score, the ligand interactions are scored the same as interactions in the rest of the protein except with a 2X amplification, in this case. The way the score works (more or less), is that there are various components that make up the score function (ie. terms that try to account for solvation, electrostatics, how likely a residue will take a certain rotamer position given its context, van der waals interactions, hydrogen bonding, etc…) All of these terms are basically weighted according to their importance (figured out via many methods, but one of which is by seeing how good the automatic algorithms are at reconstituting a native sequence/structure) So all these components are summed up for each residue (which makes up the residue score when you press tab over it), and all of the residue scores are added up to give the entire puzzle score. (which is why you can get "higher" scores on proteins with more residues.) The ligand is basically treated as another residue in this case, except that the scores attributed to it are upweighted.

I hope that makes sense! For sure let me know if I can clarify parts of that. (I wasn't sure if that was what you were asking, so I made it "brief"… sort of.)

-Austin

[marie_s]

I think my alternative solution is better then my top scoring solution : no ASP, GLU, ARG, LYS, HIS.
How can I choose what solution I submit ?
I save it at "2".

[beta_helix]

As Austin mentioned:

"We do, however, log every move that is made, so even if you don't get the highest score and those tasty points, if your design is good, we'll find it."

If you are referring to the CASP9 Design Contest,
http://fold.it/portal/node/988332#comment-8562

That is the puzzle where we plan to examine your top scoring solution, but that was mostly for you not to worry about the scores of other players for that contest.

Sorry for the confusion, and if you find a cool shape for the contest (that doesn't have your highest score) feel free to let us know and post it in that Forum link!