1956: Influenza HA Binder Design: Round 2

Closed since about 5 years ago

Summary

• Created: February 12, 2021
• Expires: February 19, 2021 at 23:00 UTC
• Max points: 100

Description

Design a protein to bind to influenza virus! This puzzle has a Move Limit of 250 moves; after that, you will be unable to improve your solution, but you can restart the puzzle to reset your move count. The Move Limit is meant to encourage players to try multiple solutions to the puzzle, instead of spending a lot of time optimizing a single solution.



The hemagglutinin (HA) protein is displayed on the surface of the influenza virus, where it can bind to receptors on human cells. Once the HA protein binds to a human receptor, the entire HA protein changes shape, springing open to trigger membrane fusion so that the virus can infect the human cell. We want to design a protein that can bind to the pre-fusion shape of HA, to stop it from springing open and thereby blocking infection.



In this puzzle, we've presented a section of the target HA protein in the pre-fusion shape. The backbone and most of the sidechains are frozen, except at the binding site, where flexible sidechains are shown in color. Players can design a new protein that can bind to these sidechains, stabilizing this pre-fusion shape. In order to bind the HA 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! Beware the large sugar sidechain next to the binding site, which has lots of polar atoms that can form unstable BUNS if you are not careful. See the puzzle comments for Objective details.

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• 5. Anfinsen_slept_here 85 pts. 15,876
• 6. Enzyme 81 pts. 15,860
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• 8. fpc 74 pts. 15,828
• 9. frood66 71 pts. 15,734
• 10. Galaxie 68 pts. 15,697

Comments

[bkoep]

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

Contact Surface Metric (max +1000)
Measures how much of your binder surface is in close contact with the target protein. The goal Contact Surface is 400 or more.

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

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 and helices.

Move Limit
Scores become invalid after 250 moves. Players are encouraged to restart the puzzle and try a new solution!

[NinjaGreg]

I had formed a 2 helix 3 sheet secondary structure, frozen the sheets and helices, un selected everything, and tried to wiggle. The loop counter just starting its rapid ascent, and when I stopped it I saw the notice that wiggle cost a move. I tried selecting just the designable part (65 segments), and it did it again. I tried exiting the client completely (it was the only one running), and starting again, but got the same result. Anyone else seeing this?

[LociOiling]

Puzzle 1956 has a Move Limit filter, a feature previously seen in sketchbook puzzles.

Previously, these puzzles had "Sketchbook" in the title.

1802: Sketchbook Symmetric Trimer Design: 70 Residues, which expired 27 February 2020, was the last puzzle of this type. So the Move Limit will be new to most pandemic-era players.

There were previously a number of problems with what counted as a "move". For example, loading saved secondary structures counted as a move the last time I checked. Several other commands which don't actually move anything also counted against the Move Limit.

The move count is saved with the pose. So if you manually save a solution, the move count will be the same if you load it again. Also, undo restores the previous move count along with the previous state of the protein.

It's possible for recipes to count moves, but there's not a direct interface to get the number of moves remaining. Instead, recipes must keep their own counter, subtracting a move for each shake, wiggle, mutate, and so on.

Some recipes have adapted to the move limit by offering a "minimum gain" or "throwback" option. The idea is to skip small gains, restoring a previous pose. The quicksave and quickload commands are used to save and restore the pose.

Recipes can also check the status of the Move Limit condition. It's possible it changes to "not satisfied" when the move limit is exceeded. I'm actually not sure about that, but I'll test it and report back.

[milkshake]

I have seen that before on other puzzles. I took it to mean that the optimizer is stuck in a local minimum, but it could have another (more buggy) source as well. I'll bring it up with the other devs.

[grogar7]

I have been using the move tool extensively to place my designed protein in a good position relative to the target and have not been charged for any moves. Also, I used the wiggle sidechains tool and was not charged for the move.

[LociOiling]

The nice part about this puzzle is that moving the protein through space no longer costs moves. Previously, each click on the move tool would cost you.