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1953: Influenza HA Binder Design

Closed since about 5 years ago

Intermediate Overall Design

Summary

Created
February 05, 2021
Expires
Max points
100
Description

Design a protein to bind to influenza virus! 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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Comments

bkoep Staff Lv 1

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.

Anfinsen_slept_here Lv 1

Can you please comment more on residue 13. It seems to have a post-translational modification.(sialic acid?) Should we be attempting binding in its neighborhood? Will it count as BUNS if we bury it and don't h-bond to it?

bkoep Staff Lv 1

Yes, residue 13 is glycosylated with a large glycan. We've included the two GlcNAc sugars that are resolved in a crystal structure of HA (4FNK), but these two sugars are only a stub of the long polysaccharide that is actually attached at this position. (The rest of the rest of the glycan is not included in the crystal structure.)

The sugars are very close to the binding site, and may be difficult to avoid completely. However, I do not recommend trying to design interactions between your binder and the glycan. The glycan does not offer much hydrophobic surface area for tight binding. It also has lots of polar atoms which can become unstable BUNS if they are buried under your binder without forming H-bonds. Unfortunately, the BUNS objective seems to have some problems with the glycan (since it is not a typical protein residue), so you may have to look out for BUNS by eye.

BootsMcGraw Lv 1

The Contact Surface Metric is supposed to provide a maximum 1000 bonus points for a CS value of 400. The bonus goes well over 1000 points, which is why you are seeing some insanely high scores on the leaderboard.

I have a CS value of 513, and it has given me 6133 bonus points. I thought this value was capped on the last puzzle with the CSM.

bkoep Staff Lv 1

It looks like an error in the puzzle setup, sorry! We'll leave this puzzle up as is, since it may still give us good designs, but this should be capped in future puzzles.