1261: Tuberculosis Challenge - Phase 2: Predicted Contacts

Closed since over 9 years ago

Summary

• Created: July 18, 2016
• Expires: August 01, 2016 at 23:00 UTC
• Max points: 100

Description

NOTE: The expiration date for this puzzle has been extended by 1 week, due to the size and complexity of the problem.



This is a follow-up puzzle for Puzzle 1258, now with Predicted Contacts to help guide your folding! See the blog for information on using the contact map. You can see the predicted contacts for this protein by clicking the Contact Map button in the Main menu (Selection Interface) or in the Actions tab (Classic Interface). You will notice that different contacts are shown in different shades of green, with brighter green contacts indicating stronger predictions. Players will be able to load in manual saves from Puzzle 1258 and use them as a starting point here. This protein is currently being investigated for drug discovery against Tuberculosis (TB), although its structure is still unknown.



Sequence:

MLTFVARPYLIPSESMEPTLHGCSTCVGDRIMVDKLSYRFGSPQPGDVIVFRGPPSWNVGYKSIRSHNVAVRWVQNALSFIGFVPPDENDLVKRVIAVGGQTVQCRSDTGLTVNGRPLKEPYLDPATMMADPSIYPCLGSEFGPVTVPPGRVWVMGDNRTHSADSRAHCPLLCTDDPLPGTVPVANVIGKARLIVWPPSRWGVVRSVNPQQGR

Top groups

• 1. Anthropic Dreams 100 pts. 14,623
• 2. Contenders 79 pts. 12,738
• 3. Beta Folders 61 pts. 12,548
• 4. Go Science 47 pts. 12,154
• 5. Void Crushers 35 pts. 11,761
• 6. Gargleblasters 26 pts. 11,503
• 7. Deleted group pts. 11,365
• 8. L'Alliance Francophone 14 pts. 11,169
• 9. Italiani Al Lavoro 10 pts. 10,430
• 10. Deleted group pts. 9,907

Top soloists

• 1. Susume 100 pts. 14,561
• 2. grogar7 99 pts. 13,188
• 3. gitwut 97 pts. 12,713
• 4. retiredmichael 95 pts. 12,354
• 5. bertro 93 pts. 12,276
• 6. Bruno Kestemont 91 pts. 12,154
• 7. Galaxie 89 pts. 12,151
• 8. dembones 88 pts. 11,935
• 9. Timo van der Laan 86 pts. 11,761
• 10. Fetztastic 84 pts. 11,730

Comments

[Bruno Kestemont]

Do you think all of them, or only some of them, should be reproduced in or models?

[toshiue]

Predicted 3D models assisted by predicted contacts, and predicted contact map (for 1261, not 1262) … fwiw
http://raptorx2.uchicago.edu/ContactMap/myjobs/74298828_105939/

[Bruno Kestemont]

Interesting source !

[free_radical]

I think that those contacts are the closest clues to how this protein is folded and should be remained. In my own modeling of low homology models, I always try to keep the binding pocket and residues used in catalysis as close as possible. This is because in low homology models, the binding pocket is almost always very well conserved.

Here is an example of what was done on a project I worked on. At the time, the human serotonin protein did not have a crystal structure and the closest homolog crystal structure had ~25% similarity. However, if you looked at the binding pocket residues (binding pocket residues identified through mutational/experimental studies), the similarity jumped up to ~60%. Therefore, when we modeled the protein, we tried real hard to make sure all those residues were kept in contact.

[free_radical]

Hi jeff101,

Both of those articles provide some clues :)

[Susume]

After reading several articles and looking at homologs, as near as I can tell the following are likely conserved. I am not a biologist, so take it with a grain of salt:

93 lys and 15 ser - these form the "catalytic dyad" (part of the active site) and should be close enough for their tips to form a hydrogen bond.
13 ser may also be involved, so it may be good to have it near 93 as well.
93 lys is likely partially buried rather than on the surface of the protein, though its tip needs to be near the surface.
156 gly is in contact with 93 lys, close enough that if you were to put a sidechain on the gly it would clash with the lys sidechain.
162 ser sidechain is in contact with both 93 lys and 15 ser sidechains, and is part of the active site.
164 asp and 166 arg sidechains form a salt bridge, which I think shows up in foldit as a hydrogen bond. This helps shape the backbone so that 162 ser is in the right place.
These sidechains may form a hydrophobic pocket (called s1) near the catalytic dyad:
16 met, 92 val, 20 leu, 11 ile
These sidechains may form another hydrophobic pocket (called s3) near the catalytic dyad:
9 tyr, 11 ile, 31 ile, 50 val, 92 val, and the beta carbon of 90 asp
Our part of the protein may have a side with exposed hydrophobics for sticking against the membrane (this is in addition to the part of the protein that stays embedded within the membrane, which has been left off of our model).

[actiasluna]

With the articles coming in, and more information, could we please have a third round for this puzzle? Those of us with less science background could learn much from another try.

[Skippysk8s]

I'm not a scientist. I tried a sheet plane with helices on either side in phase one, which didn't do too badly. it could likely be improved. I don't even mind a scientist taking my phase one fold and showing how to improve it.
Sadly, I had to quit this puzzle days ago as a solo player. the number of residues plus the contact map made it too large for my cpu.
We'd love to put all hands on deck. so if you could take something, show us how to apply the science, many of us would be happy to try and refold
Skip

[jeff101]

I would appreciate it if the next few Phases of this Challenge keep letting us load saves from all previous Phases (Puzzles 1258 and 1261 so far).

Thanks again!
Jeff

[Susume]

The blog post said there would be a phase with starts based on homologs. I hope there will be at least one phase with both homolog starts and contacts, because applying the contact data seems like the best way to modify a homolog template to make it more accurate.