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

• 11. BOINC@Poland 11 pts. 10,996
• 12. turkish voluntered 9 pts. 10,988
• 13. Deleted group pts. 10,987
• 14. Natural Abilities 5 pts. 10,986
• 15. Deleted group pts. 10,982
• 16. L'Alliance Francophone 3 pts. 10,981
• 17. Crunching Family 2 pts. 10,970
• 18. Boinc.be 1 pt. 10,937
• 19. Czech National Team 1 pt. 10,928
• 20. Oma Gawd 1 pt. 10,890

Top evolvers

• 1. CharlieFortsConscience 100 pts. 11,075
• 2. Mark- 85 pts. 11,073
• 3. Bletchley Park 71 pts. 11,071
• 4. mimi 60 pts. 11,070
• 5. auntdeen 49 pts. 11,063
• 6. adrock2999 41 pts. 11,059
• 7. Deleted player pts. 11,059
• 8. Wilderbeast52 27 pts. 11,046
• 9. dimension9 22 pts. 11,046
• 10. compotatoj 17 pts. 11,038

Comments

[beta_helix]

Here are some tips you can follow to increase your chance of us selecting and testing your design:

1) Don't bury the TNT ligand too deeply, this may disrupt the overall protein structure.

2) Avoid using charged residues (ASP, GLU, ARG, LYS, HIS) to make hydrogen bonds when possible (although one or two may be fine).

3) Make sure that the tail of the ligand has a way to get out of the binding site. The tail is the end of the ligand that is directed away from the center of the protein initially. (The linker isn't modeled in, but that tail is connected to more atoms, so make sure it can get out!)

[Dj-P]

Everyone who joins the group Go Science?

[steveB]

So when this is finished, you plan to get a protein that one of us crazy non scientists has designed, take it to the wet lab, and then see what happens when you throw it at a piece of TNT.

Brave. Very brave :)

[xiando]

Thank you both for your comments in the puzzle description and in the comments down below here. The both offer some helpful information.

If I could vote more than once there'd be yet another thumbs up.

[beta_helix]

Austin,

thanks for the detailed reply. That was exactly what was looking for. When I first got into this program, (well before my posted start date for this simulacrum me) I established a set of beliefs based partially on inchat discussion, partially on a wide range of preconceptions, about what was and wasn't the right way to think about how the protein needs to be "modified" for best purposes of the actual design/refinement/fold in the lab, some I think on target, some way off base. Posts like the ones you just made, I believe (if people read it thoroughly) will benefit the overall conceptualization about what needs to be done to make a good effort, whether high or low scoring… At least people like me, who can become fuddled by the various paradigms others are using to succeed (whatever that means).

I also really appreciate the comment about viewing all the solutions. It has concerned me that perhaps only top scores were evaluated. That goes a long way to remedying some or perhaps most of my worry about "productive time spent".

Thanks again. Very very helpful to me, and hopefully to others as well.

[xiando]

This is the first design puzzle I've attempted, and I'm not quite sure of the goal (aside from ftw points)

From the descriptive, it's seems* that the tail (at least) needs a way out of the protein. What's not quite so clear about the ligands in general is in regards to deformations in the ligand structure during the "adjustment" of the design (since presumably this is truly a refinement rather than a redesign puzzle at least in the ?polypeptide? (backbone) layout.

Specifically, is one of the goals to maintain the initial structural conformation of the ligand? As opened, the ligand is very monoplanar (aside from the "Y" structures on the head end.

Some adjustments result in the tail end curling slightly, but it would be very useful to understand if this is an indication of bad judgement with respect to "adjustments"…grrr tweaks, I mean tweaks! (not the foldit function, the common-english action of slightly modifying something) or just a necessary result of the transformations?

*having said that, by getting out of the binding site, I'm not exactly sure if that means literally getting out of the protein or just to another part of the protein. My assumption is/was that it means "a clear path to the outside", but it would be helpful to understand that statement in slightly more detail.
Perhaps it has to do with what a binding site is. Maybe a brief parenthetical ( a short description enclosed by parenthesis) after the use of something like "binding site", which for noviats and non protein scientists might be a bit opaque otherwise…

Also on a side note, I'm not quite clear on the "mutate side chains" function. Is that essentially an automatic version of "manually changing a single side chain into another" function from design mode that acts on the whole protein? I accidentally hit it instead of something else and noticed my score jumped a few points. (16 points to be exact)

thanks

[austinday]

Why can we not mutate any residue?

I mean, if the goal here is to design a better binder for TNT and if the basic shape you gave us is to be used as a starting point, why can we not modify all of the positions?

What if (for example) we wanted to improve the rigidity (cross bonding) between the inner sheets and the outer helices?

What if we wanted to replace the outer helices with sheets in some places?

If we could modify the outer shell, we may be able to build a better cage that would allow us to push the ligand binding sites closer to the edge. With our detectors nearer to the surface, we would need a shorter "tail" and we would be more likely to catch the target molecule.

Am I just dreaming?

[xiando]

Austin,

thanks for the detailed reply. That was exactly what was looking for. When I first got into this program, (well before my posted start date for this simulacrum me) I established a set of beliefs based partially on inchat discussion, partially on a wide range of preconceptions, about what was and wasn't the right way to think about how the protein needs to be "modified" for best purposes of the actual design/refinement/fold in the lab, some I think on target, some way off base. Posts like the ones you just made, I believe (if people read it thoroughly) will benefit the overall conceptualization about what needs to be done to make a good effort, whether high or low scoring… At least people like me, who can become fuddled by the various paradigms others are using to succeed (whatever that means).

I also really appreciate the comment about viewing all the solutions. It has concerned me that perhaps only top scores were evaluated. That goes a long way to remedying some or perhaps most of my worry about "productive time spent".

Thanks again. Very very helpful to me, and hopefully to others as well.

[saksoft2]

Austin,

thanks for the detailed reply. That was exactly what was looking for. When I first got into this program, (well before my posted start date for this simulacrum me) I established a set of beliefs based partially on inchat discussion, partially on a wide range of preconceptions, about what was and wasn't the right way to think about how the protein needs to be "modified" for best purposes of the actual design/refinement/fold in the lab, some I think on target, some way off base. Posts like the ones you just made, I believe (if people read it thoroughly) will benefit the overall conceptualization about what needs to be done to make a good effort, whether high or low scoring… At least people like me, who can become fuddled by the various paradigms others are using to succeed (whatever that means).

I also really appreciate the comment about viewing all the solutions. It has concerned me that perhaps only top scores were evaluated. That goes a long way to remedying some or perhaps most of my worry about "productive time spent".

Thanks again. Very very helpful to me, and hopefully to others as well.

[infjamc]

The main reason that we might not want to mutate the outer shell is that the structure could change considerably. In this puzzle, the backbone is held rigid– but when the mutated folding actually folds, the rigidity doesn't actually apply… which means that you risk changing the structure too much by modifying the outer shell. In fact, even mutating only the inner residues is a risk because sometimes a difference of a single residue is enough to prevent it from functioning properly. (Example: the Delta F508 mutation, which results in the removal of a single residue from a human protein, is a common cause of cystic fibrosis.) This is part of the reason the resulting structure has to be re-checked with actual experimentation.

==> That being said, redesigning the outer shell is something that can be considered if necessary. Ultimately, it boils down to the issue of efficiency– namely, whether the increase of complexity (larger search space) is worth the extra effort of coming up with an outer structure from scratch.