1913: MERS-CoV Binder Design: Round 3

Closed since over 5 years ago

Summary

• Created: November 06, 2020
• Expires: November 12, 2020 at 23:00 UTC
• Max points: 100

Description

Design a binder for the viral spike of MERS-CoV! This puzzle is similar to Puzzle 1910, except that the Foldit Metrics will award increasing bonuses as you improve the DDG, SASA, and SC of your solution. The Metrics are slow to compute and run in the background, so gameplay may be different from regular puzzles. See the blog for more info about Foldit Metrics.



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. 15,529
• 2. Go Science 68 pts. 15,387
• 3. Anthropic Dreams 44 pts. 15,035
• 4. Marvin's bunch 27 pts. 14,968
• 5. Contenders 16 pts. 14,807
• 6. Beta Folders 9 pts. 14,766
• 7. Void Crushers 5 pts. 14,708
• 8. BOINC@Poland 3 pts. 14,232
• 9. L'Alliance Francophone 1 pt. 13,965
• 10. Hold My Beer 1 pt. 13,897

Top soloists

• 71. zo3xiaJonWeinberg 3 pts. 12,737
• 72. HMK 3 pts. 12,669
• 73. Trajan464 3 pts. 12,619
• 74. AlkiP0Ps 3 pts. 12,532
• 75. Beany 3 pts. 12,483
• 76. hada 2 pts. 12,430
• 77. RyeSnake 2 pts. 12,426
• 78. BarrySampson 2 pts. 12,308
• 79. illex 2 pts. 12,258
• 80. JasperD 2 pts. 12,225

Comments

[bkoep]

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.

SASA Metric (max ???)
The solvent-accessible surface area that is lost upon binding. The target SASA is 1500 or more.

DDG Metric (max ???)
The predicted binding energy of your design. The target DDG is -40.0 or less.

SC Metric (max +100)
Measures how well your binder fits the contours of the target surface. The target Shape Complementarity is 0.60 or more.

[BootsMcGraw]

I found that is was possible to design a protein that met the criteria for all three metrics, but it was so fragile that even breathing on the protein caused a metrics meltdown.

The new metrics should prove less frustrating to most players, since SASA of 1500 and DDG of -40 don't seem realistic. (Are they? Someone please explain how these thresholds were derived.)

The problem is: Is a SASA of 750 half as good as one of 1500? Is a SASA of 500 a third as good? 150 one tenth as good? At the lower end of the spectrum, these values are probably meaningless, and there is likely some threshold value below which the SASA doesn't matter… it ain't sticking to the target, and above which the protein can stick to the target, the higher the SASA, the better the fit.

The same general principal applies to DDG and SC.

I propose that the scoring for the three metrics be modified, starting with zero additional points at some minimum, non-zero value, and increasing based on how much more than the minimum the player can reach, up to some limit.

e.g. 0 points for SASA under 1000, 5 points for each increase of 1 A up to 1500, no additional increase if the SASA exceeds 1500.

Again, the same general principal applies to DDG and SC.

[bkoep]

These thresholds are empirical. They come from experiments (like this one) with designed protein binders at the IPD. Scientists have found that successful binders tend to meet these thresholds, and that experimental success rates improve if we focus on only designs that meet the thresholds.

For that reason, we probably will limit testing to designs that meet the thresholds; we are less interested in designs that fail the thresholds. However, it is not clear that there are benefits in exceeding the thresholds. To maximize our chance of success, we want to generate as many designs as possible that meet the thresholds.

It is a very difficult design problem, but these numbers can be achieved. Some of our previous blog posts (like here and here) display some designs that meet the thresholds.

I like your proposed scoring scheme! In fact, our most recent update should allow us to use a similar scoring scheme to the one you suggest, with a bonus that ramps up to the threshold and then caps off.