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1859: Coronavirus Anti-inflammatory Design: Round 7

Closed since about 2 years ago

Intermediate Overall Design


July 02, 2020
Max points

Design an anti-inflammatory protein for COVID-19! The Buried Unsats Objective has been reactivated and it will incur a 60 pt penalty for each BUNS atom. If your designed protein creates Buried Unsats, then it will be less likely to fold and bind to the target. (Note that this target protein includes 15 buried unsats that players may be unable to fix.) See the blog for more details about buried unsats, and for helpful tips to make a successful protein binder! Players will be unable to load solutions from previous puzzles.

Many COVID-19 complications are caused indirectly by the virus, and result from a severe over-stimulation of the human immune system. This kind of immune over-stimulation is commonly called a "cytokine storm." During a viral infection, immune cells normally release signaling proteins called cytokines, which inform the rest of the immune system about the infection and trigger inflammation. The inflammation is supposed to help the immune system fight off the infection, but too much inflammation can result in sepsis and organ failure.

One proposed strategy for treating serious COVID-19 cases is to prevent the "cytokine storm" by blocking certain cytokine signals. We want to design a protein that could block cytokine IL6, by binding to the IL6 receptor (IL6R). For more details, see our YouTube video about blocking the cytokine storm.

In this puzzle, players are presented with the binding site of IL6R, which receives cytokine signals and triggers inflammation. The backbone and most of the sidechains are completely frozen, except for sidechains at the cytokine binding site. In order to bind the IL6R target, designs will need to make lots of contacts and H-bonds with the target protein at this binding site. 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.

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bkoep Staff Lv 1

Buried Unsats (max +100)
Penalizes 60 points for each polar atom that cannot make any H-bonds. Note that the frozen target includes 15 buried unsats that may be impossible to satisfy.

Residue Count (max +275)
Penalizes extra residues inserted beyond the starting 151, at a cost of 55 points per residue. Players may use up to 156 residues in total.

Core Existence (max +1000)
Ensures that at least 25 percent of residues are buried in the core of the monomer unit.

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)
Penalizes all CYS residues. Penalizes GLY, ALA residues in sheets. Penalizes GLY, ALA in helices.

Bruno Kestemont Lv 1

I've a problem with the new Buried Unsats filter. The protein tends to disassemble (because there are less buried unsats when the monomers are separated).

Ther should be a core existence complex filter (or wathever) in order to counter this problem.

bkoep Staff Lv 1

I think this is working as intended. If BUNS are created when the symmetric copies come together, that means your complex is unlikely to assemble–no matter what the core complex looks like. It's more important to focus on satisfying BUNS than increasing the complex core.

mathwins Lv 1

They are not capped in this puzzle. Satisfying target BUNS adds 60 points to the total of bonus points.

But more importantly, if I satisfy target BUNS manually and then wiggle it a bit, it sometimes happens that it "removes" those satisfied BUNS.

Does that mean, it is not stable/sticky enough or how do I have to interpret this behavior?

agcohn821 Staff Lv 1

Hi there! Thank you so much for your question–I have passed it along to the team.

bkoep Staff Lv 1

Yes sometimes Wiggle will create BUNS that you've manually satisfied. This is not a problem with the stability/stickiness of your solution. It is a problem with Wiggle, and unfortunately it is not an easy problem to solve.

Under the hood, Wiggle tries to improve your score by optimizing lots of different score terms at once (like clashing, H-bonding, and backbone geometry). However, Wiggle doesn't know about BUNS. This means that sometimes Wiggle will sometimes cause new BUNS problems while it is trying to optimize the other score terms.

This is a tricky problem to solve. Since the BUNS Objective is not continuous (there's no such thing as 1.2 BUNS), it is not compatible with Wiggle. My best recommendation is to try adding bands to keep BUNS satisfied.