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1675: Integrin Antagonist Binder Design: Round 3
Status: Closed

Summary

Name: 1675: Integrin Antagonist Binder Design: Round 3
Status: Closed
Created: 05/16/2019
Points: 100
Expired: 05/23/2019 - 23:00
Difficulty: Advanced
Description: Help design a protein binder for cancer therapy!

Integrins are cell adhesion receptors that are normally inactive on the surface of cells. Once activated by a ligand, integrins can induce changes in cell cycle, growth factor signaling pathways, cytoskeletal organization, and movement. Recently, integrins have emerged as a key target in anti-cancer therapy as integrins are involved in promoting tumor metastasis and cancer blood vessel formation. Integrin antagonists have already proven successful in halting invasion and migration of tumors.

The challenge for Foldit players is to help design a binder for the integrin binding site that will induce full antagonism.

In the previous iterations of this puzzle, we excised the binding portion of the integrin as the target. For the ligand, we froze the 9 amino acid domain where the RGD loop resides, and allowed Foldit players to design 65 residues flanking the frozen loop domain. In Round 1, Foldit players reported wiggle/shake times were too long, due to the puzzle size. In Round 2, we reduced the puzzle size and added a core-filter bonus to ensure good folds. The puzzle solutions proved to be promising!

Many of the best scoring designs made great contacts with the integrin target, but lacked a good hydrophobic core, which makes them unlikely to fold in solution. While making more contact with the target is good, hydrophobic core interaction is an important driving force in the folding of soluble protein domains. That being said, the solutions that had great cores often lacked stabilizing contact with the target outside of the loop.

As such, we've revised the objectives in this puzzle. High scoring solutions should have stable cores. Many previous solutions had too much alanine in the core, and not enough larger hydrophobic residues, so we've adjusted the score function to discourage alanine. Second, the proteins should make at least one other major contact with the target. Let’s give cancer a good fight!
Categories: Design, Overall

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Comments

frood66's picture
User offline. Last seen 17 hours 30 min ago. Offline
Joined: 09/20/2011
Groups: Marvin's bunch
why the lack of info on this page?

The filters are not properly explained - which would be de rigour.

Also this is the 3rd puzzle on this - yet no ability to load from previous puzzles.

Perhaps the set up for this puzzle dictates that previous puzzles cannot be loaded - then please say so FC.

All the above would, at least, be polite.

bkoep's picture
User offline. Last seen 18 hours 49 min ago. Offline
Joined: 11/15/2012
Groups: None
Objectives

Sorry for the lack of info—that was simply an oversight! Objective details are below.

We are not allowing players to load solutions from previous puzzles, because we would prefer for players to try new approaches and designs (to improve design diversity), rather than spend time refining previous solutions.

Residue IE Score (max +500)
Monitors that all PHE, TYR, and TRP residues are scoring well.

Core Existence (max +820)
Ensures that at least 25% of residues are buried in the core of the designed binder.

Residue Count (max +275)
Penalizes extra residues inserted beyond the starting 60, at a cost of 55 points per residue. Players may use up to 65 residues in total.

frood66's picture
User offline. Last seen 17 hours 30 min ago. Offline
Joined: 09/20/2011
Groups: Marvin's bunch
Hmmmm

So actually U R saying that the solutions from the previous puzzle were not that promising.

This appears to contradict the main puzzle description.

Please be clear FC - else U waste valuable computer time....respect for that would be nice. ;)

bkoep's picture
User offline. Last seen 18 hours 49 min ago. Offline
Joined: 11/15/2012
Groups: None
Misunderstanding

I don't see any contradiction. Maybe I misunderstand you?

Often, when we allow loading from previous puzzles, we see that players spend most of their efforts refining their previous solutions. Rather than start over with a new idea, they start from their previous high-scoring solution—gradually improving the score but rarely making substantial changes to the design.

Many solutions from the previous Puzzle 1664 look very good already, so we see no reason for players to spend more time refining those solutions. It seems to me that would be a waste of resources.

Instead, we'd like for players to focus on trying new ideas, generating new and different designs with greater diversity.

Joined: 06/24/2008
Groups: Void Crushers
Thanks

I was just about to ask what to ask for these!

Joined: 05/26/2008
Groups: Hold My Beer
When we get to round 4....

Would it be possible in the next round to lock the bacbone but let us manipulate the sidechains ? part of the issue I see is it is difficult to create a core because there are limited number of pockets where things can be tucked in, and it is difficult to create contacts because sidechains are locked in place which pushes the larger structures out and away.

Hope this makes sense

sgorji's picture
User offline. Last seen 10 weeks 1 day ago. Offline
Joined: 04/01/2019
Groups: None
Re:

This is an excellent suggestion. In the first iteration of this puzzle, we locked the backbone of the target but let players manipulate side chains. Unfortunately, this extended wiggle/shake times. In the second iteration, we froze both the backbone and the side-chains of the target entirely, but this may have exacerbated finding nice core pockets. In the next iteration, we can free up at least some of the side chains in the target, especially those around the binding core. Definitely worth pursuing! Thanks!

Joined: 06/06/2013
Groups: Gargleblasters
puzzle crash

I opened blueprint to try to shift a loop on a "solution" and the puzzle crashed....

At one point I tried to form some of the non-frozen part into helix and ended up with a big chunk of the "frozen" part also turning into helix which I could not undo

I still have no idea what I'm doing..tho I thought I was trying to bind protein near anything that gave access to the little orange dots.

I'll wait for more instruction and some examples as I'm stuck

Skip

LociOiling's picture
User offline. Last seen 6 hours 4 min ago. Offline
Joined: 12/27/2012
Groups: Beta Folders
Screenshots of results

See Puzzle 1675 screenshots on the Foldit wiki.

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Developed by: UW Center for Game Science, UW Institute for Protein Design, Northeastern University, Vanderbilt University Meiler Lab, UC Davis
Supported by: DARPA, NSF, NIH, HHMI, Amazon, Microsoft, Adobe, RosettaCommons