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1871: Coronavirus Anti-inflammatory Design: Round 9
Status: Closed

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bkoep's picture
User offline. Last seen 19 hours 13 min ago. Offline
Joined: 11/15/2012
Groups: Foldit Staff
Objectives

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, SER, THR in helices.

spvincent's picture
User offline. Last seen 9 hours 52 min ago. Offline
Joined: 12/07/2007
Groups: Contenders
It's likely this question has

It's likely this question has been asked before, but why not use Hydrogen Bond Networks in these types of puzzles? Maybe its a limitation in Foldit but it seems they'd be useful in making the binding specific.

bkoep's picture
User offline. Last seen 19 hours 13 min ago. Offline
Joined: 11/15/2012
Groups: Foldit Staff
Great question!

We absolutely could reward H-bond Networks in these puzzles, but I think the BUNS objective is more appropriate.

Ultimately, the specificity is driven by polar atoms at the interface. The polar atoms fend off unintended binding partners, because these atoms will become BUNS if they are not satisfied by complementary polar atoms on the target.

Specificity is a big problem in symmetry puzzles, because we can design both sides of the interface. This means we have the power to design interfaces that are entirely hydrophobic (and these typically have the best Foldit score). We specifically want to encourage the addition of polar atoms at the interface, and this is the role of the H-bond Network objective. The BUNS objective alone does not encourage new polar atoms.

This IL6R binder puzzle is different. The target IL6R protein already has lots of polar atoms at the interface. It is basically impossible to design an entirely hydrophobic interface -- any top-scoring solution will have to bury some polar atoms on the target, so we are very worried about creating BUNS. The BUNS objective will force us to add polar atoms at the interface, and we think this alone should create the specificity we want. There is no need to encourage more polar atoms with the H-bond Network objective.

Joined: 12/06/2008
Groups: Contenders
High score does not equal best design.

I currently have the high soloist score on this puzzle. I have no sidechains from my designed protein binding to any sidechains of the target protein. Yet I have thirteen BUNS (and there are supposedly fifteen we can't fix).

Is this a flaw in the scoring? Isn't the goal to create a protein that will bind with this target? I don't think I've created one, yet my score implies otherwise.

bkoep's picture
User offline. Last seen 19 hours 13 min ago. Offline
Joined: 11/15/2012
Groups: Foldit Staff
Work in progress

I'll have to take a look at your specific solution, but you're right that the Foldit score alone is probably not sufficient for binder design. There are several binder metrics that other researchers have found useful for binder design, and these will be available in Foldit soon.

It sounds like you've found a way to bind to the target without burying any polar atoms at the interface (which is great!). There is a possibility that the BUNS objective is missing some buried polar atoms -- the BUNS objective relies on some approximations that trade accuracy for speed. But, most likely, if the BUNS objective fails to flag any atoms at your binder interface, that means all of the polar atoms are satisfied or able to make H-bonds with the surrounding water.

Joined: 12/06/2008
Groups: Contenders
Alanine, alanine, my kingdom for an alanine!

So when are we going to get to start designing proteins with alanines in the helices, like in real life?

If you really don't want to see alanine-rich helices, aan't you add a penalty function that allows no more than, say, ten percent of helix residues to be alanines?

bkoep's picture
User offline. Last seen 19 hours 13 min ago. Offline
Joined: 11/15/2012
Groups: Foldit Staff
Yes!

That's exactly what we'd like to do, and it is on the to-do list. Currently it's taken a back-seat to other priorities for protein design. That penalty shouldn't be too difficult to add (although we do need to make sure it plays nicely with the Mutate tool); hopefully we will be able to tackle it soon.

APPAAP's picture
User offline. Last seen 2 days 14 hours ago. Offline
Joined: 04/25/2020
Groups: None
BUNS

The BUNS score that have achieved is more than +100 noted in the objectives by bkoeb. I have 13 buried unsats up to now.

APPAAP's picture
User offline. Last seen 2 days 14 hours ago. Offline
Joined: 04/25/2020
Groups: None
BUNS

Correction. ''Noted in the objectives by bkoep'' is the correct.

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