1920: MERS-CoV Binder Design: Round 5

Closed since over 5 years ago

Summary

• Created: November 21, 2020
• Expires: November 27, 2020 at 23:00 UTC
• Max points: 100

Description

Note: Due to strange behavior and frequent hangs, this puzzle has been reduced to zero points. Players should not feel compelled to play it for competitive reasons. However, the results of this puzzle have exceptional scientific value, so the puzzle will remain active for those who wish to keep working. Once we find and fix the bugs, we intend to repost the puzzle so that players may load previous work and continue competitive play.



Design a binder for the viral spike of MERS-CoV! The latest update lets us use DDG and Contact Surface as regular Objectives, instead of as background Metrics. Contact Surface captures some of the same info as both SASA and SC, and is even better at selecting successful binder designs in the lab. Contact Surface favors binders with large interfaces that closely follow the contours of the target. DDG and Contact Surface have a ramped bonus; as you improve DDG and Contact Surface, you will get an increasing bonus until you reach the threshold of DDG < -40 or Contact Surface > 400, and then the bonus will be capped.



MERS is a respiratory disease similar to COVID-19, and is caused by a related coronavirus. There have been several MERS outbreaks since 2012, but there is still no treatment has been developed for the disease. The MERS-CoV virus is coated with a spike protein that recognizes the human protein DPP4, which is found on the surface of lung cells. A protein that binds to the MERS-CoV spike could be used as a drug to block DPP4 recognition and slow viral infection.



In this puzzle, players are presented with the binding site of the MERS-CoV spike protein. The backbone and most of the sidechains are completely frozen, except for flexible sidechains at the binding site, where the spike protein normally interacts with the human receptor protein. Players can design a new protein that binds to these sidechains, blocking interactions with the human receptor. In order to bind the MERS-CoV target, designs will need to make lots of hydrophobic contacts and satisfy any polar atoms that are buried at the interface. But designs will also need to have lots of secondary structure (helices or sheets) and a large core, so that they fold up correctly! See the puzzle comments for Objective details.

Top groups

• 1. Gargleblasters 100 pts. 26,016
• 2. Go Science 71 pts. 23,864
• 3. L'Alliance Francophone 49 pts. 21,786
• 4. Contenders 33 pts. 21,186
• 5. Marvin's bunch 22 pts. 20,851
• 6. FoldIt@Netherlands 14 pts. 20,607
• 7. BOINC@Poland 8 pts. 20,545
• 8. Beta Folders 5 pts. 20,434
• 9. Void Crushers 3 pts. 20,367
• 10. Anthropic Dreams 2 pts. 20,350

Top soloists

• 1. Enzyme 100 pts. 26,016
• 2. pascal ochem 97 pts. 23,864
• 3. ZeroLeak7 93 pts. 23,580
• 4. illex 90 pts. 23,280
• 5. WBarme1234 86 pts. 22,003
• 6. jobo0502 83 pts. 21,786
• 7. mirp 80 pts. 21,461
• 8. Vinara 77 pts. 21,367
• 9. ucad 74 pts. 21,316
• 10. nspc 71 pts. 21,256

Comments

[BootsMcGraw]

And… now it locked up when I initiated a script.

Moving on to 1918b and 1919, until the hang-up problem is fixed.

[BootsMcGraw]

I was able to continue working on 1920 simply by re-booting the game. No hang-ups since.

I'm still working the puzzle, because I have a good, stable design with four hydrogen bonds to the target. The DDG is currently at -39.3, and the SC is currently at 538.

The top-scoring solution has what is obviously an incorrectly high set of objective scores. Mine are higher than I thought I might get for the configuration, and they are still improving via a script. But are my scores also invalid? Am I wasting my time using the script, when the base score (current score minus DDG and SC bonuses) is increasing very little?

Which is more important, now? Minimizing total energy? Or maximizing objective values?

[bkoep]

If you've found a solution that meets the Objective thresholds, then you should focus on the base score (or even better, start a brand new solution).

It's not clear to us that there are benefits in improving the Objective values beyond the target threshold (DDG < -40 and Contact > 400). We had intended for the Objective bonuses to plateau so that there would be no incentive for pursuing extreme Objective values. There is an error in this puzzle that allows the Contact Surface bonus to keep increasing after you pass 400; we'll be sure to correct this in future puzzles.

With your DDG and Contact values, there's no need to keep improving them. We would much prefer to have 2 solutions with DDG=-40 and Contact=400; rather than just one solution with DDG=-50 and Contact=600.