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1920: MERS-CoV Binder Design: Round 5
Status: Closed


Name: 1920: MERS-CoV Binder Design: Round 5
Status: Closed
Created: 11/20/2020
Points: 0
Expired: 11/27/2020 - 23:00
Difficulty: Intermediate
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

2Go Science23,8630
3L'Alliance Francophone21,7860
5Marvin's bunch20,8500

Top Evolvers

Top Soloists

1Enzyme 60 47 Gargleblasters26,0150
2pascal ochem 60 367 Go Science23,8630
3ZeroLeak7 60 55 Go Science23,5790
4illex 60 1164  23,2800
5WBarme1234 60 26  22,0020

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bkoep's picture
User offline. Last seen 22 min 49 sec ago. Offline
Joined: 11/15/2012
Groups: Foldit Staff

Buried Unsats (max +500)
Penalizes 60 points for each polar atom that cannot make any hydrogen bonds.

Residue Count (max +275)
Penalizes extra residues inserted beyond the starting 161, at a cost of 55 points per residue. Players may use up to 166 residues in total.

Core Existence (max +1500)
Ensures that at least 25 percent of residues are buried in the core of the monomer unit.

Interaction Energy (max +500)
Monitors that all large PHE, TYR, and TRP residues are scoring well.

Ideal Loops (max +500)
Penalizes any loop region that does not match one of the Building Blocks in the Blueprint tool. Use "Auto Structures" to see which regions of your protein count as loops.

SS Design (max +500)
Disabled use of CYS residues. Penalizes GLY, ALA residues in sheets. Penalizes GLY, ALA in helices.

DDG Metric (max +1000)
The predicted binding energy of your design. The goal DDG is -40.0 or less.

Contact Surface Metric (max ???)
Measures how much of your binder surface is in close contact with the target protein. The goal Contact Surface is 400 or more.

Joined: 01/01/2016
Groups: Gargleblasters

I don't know whether it's just me but I've hung three times on this puzzle this morning. Once after an accidental double click, once during a simple shake and once during a mutate.

Joined: 01/01/2016
Groups: Gargleblasters
OK I'm giving up on this

OK I'm giving up on this puzzle. Thought I'd give it another chance but another hang almost immediately while trying to run 'Quickfix'.

g_b's picture
User offline. Last seen 9 hours 12 min ago. Offline
Joined: 04/28/2010
Groups: None
hanging for me also

two times in about 30 minutes - puzzle or new client update?

Joined: 09/29/2016
Groups: Gargleblasters
CSM Bonus?

Hey bkoep, your description of the Contact Surface Metric indicates a Max of +1000; however, in all of the puzzles with CS active, at a value of 400 it's actually been giving +5000 (due to the fact it's a Logarithmic/Scaling bonus instead of Linear).

Is that an oops on the description, or an oops on the Filter?

bkoep's picture
User offline. Last seen 22 min 49 sec ago. Offline
Joined: 11/15/2012
Groups: Foldit Staff
Filter error

Hmm, that was an oversight in the Objective setup; we had intended for Contact Surface bonus to cap at +1000. That's a little unfortunate, but I think we will still get useful data from the puzzle, so we won't close it early.

Joined: 09/29/2016
Groups: Gargleblasters
Alright, thanks.

I actually liked the extreme of it, however, can understand why it can skew the results. :)

But yes, from what I've been experiencing with my own folds, it won't be too easy to have a low DDG and a high CS. Hopefully people will remember to still pay close attention to their other objectives (ie Core Existence and BUNS)

Joined: 12/06/2008
Groups: Contenders
At what point do the DDG and CS values become meaningless?

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's picture
User offline. Last seen 22 min 49 sec ago. Offline
Joined: 11/15/2012
Groups: Foldit Staff

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.

alcor29's picture
User offline. Last seen 16 hours 23 min ago. Offline
Joined: 11/16/2012
Hard to do

Not just slow, but hanging and crashing. and other weird things. May have to give up on it.

bkoep's picture
User offline. Last seen 22 min 49 sec ago. Offline
Joined: 11/15/2012
Groups: Foldit Staff
Thanks for the feedback

If you have more details that can help us reproduce hangs and crashes, that is always helpful!

Joined: 12/06/2008
Groups: Contenders
Puzzle is hanging up on

Puzzle is hanging up on random actions: one time for a mutate, one time for a sidechain wiggle, one time for a backbone wiggle. Three hang-ups in fifteen minutes. VERY annoying.

Joined: 12/06/2008
Groups: Contenders
And... now it locked up when

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

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

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Developed by: UW Center for Game Science, UW Institute for Protein Design, Northeastern University, Vanderbilt University Meiler Lab, UC Davis
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