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.
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 <del+1000</del> ???)
Measures how much of your binder surface is in close contact with the target protein. The goal Contact Surface is 400 or more.
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.
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?
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.
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)
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.
