Design a binder against coronavirus! The new metrics have been left out to preserve regular recipe performance, but other Objectives are still in effect. Remember, if your designed protein creates Buried Unsats, then it will be less likely to fold and bind to the coronavirus target. (Note that this target protein includes 8 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 may not load solutions from previous puzzles.
In late 2019, a new highly-infections virus emerged out of Wuhan, China. This virus belongs to the coronavirus family, and is similar to the virus that caused the SARS epidemic in 2002. Coronaviruses display a "spike" protein on their surface, which binds tightly to a receptor protein found on the surface of human cells. Once the coronavirus spike binds to the human receptor, the virus can infect the human cell and replicate. In recent weeks, researchers have determined the structure of the 2019 coronavirus spike protein and how it binds to human receptors. If we can design a protein that binds to this coronavirus spike protein, it could be used to block the interaction with human cells and halt infection!
In this puzzle, players are presented with the binding site of the coronavirus 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 coronavirus target, designs will need to make lots of hydrophobic contacts and H-bonds with the flexible sidechains at the 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.
Buried Unsats (max +20)
Penalizes 60 points for each polar atom that cannot make any hydrogen bonds. Note that the frozen target includes 8 buried unsats that may be impossible for players to satisfy.
Residue Count (max +275)
Penalizes extra residues inserted beyond the 177, at a cost of 55 points per residue. Players may use up to 182 residues in total.
Core Existence (max +2400)
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)
Disabled use of CYS residues. Penalizes GLY, ALA residues in sheets. Penalizes GLY, ALA in helices.
One he felt was rather odd, and so I asked BKoep over Discord about what Boots had asked, as well as a bit of stuff I'd been wondering myself…
I figured for those (like Boots) who aren't on the Discord server, it would be helpful for you to have access to it as well. Here is the direct link to his response, should you want or need it.
[This is basically copy-pasted from Discord. Since I don't think the comment system has a "quote" feature, I'll be putting my questions that he quoted, in bold]
. #1 Is it normal for a bunch of Serines and Threonine's that are inside a Triple Helix Monomer's core, to not be BUNS?
It depends. If the SER and THR form H-bonds with one another, then they can be satisfied. There are also some cases where a helical SER or THR will form an H-bond with the helix backbone. This isn't supposed to satisfy BUNS in Foldit, but it's worth checking on. This is great feedback for improving the BUNS Objective, and the Scientist Share should be really helpful!
. #2 Is normal for the Core Existence filter to deem a "Core" be made up, almost exclusively, by Serine's and Threonines?
The Core Existence Objective doesn't care about residue types. The objective determines if a residue is in the "core" based on its position and the density of atoms nearby. Mutating a single residue should never change its core/boundary/surface designation.
. #3 Is it normal for Mutate to not replace them with something else?
Mutate will only replace a residue if the replacement scores better. A VAL would probably have a better Hiding subscore than one of these buried SER, but the VAL might introduce new clashes that make for a net loss. If Mutate is packing your helices with a bunch of SER and THR, then the helices might just be too close together for any other residue type (since ALA and GLY are prohibited and everything else is larger).
F350, thanks for posting this. I am not a member of Discord, so I can't read the response.
With respect to point #1, I had several serines and at least one threonine in the core that were neither bonded to other atoms or to the backbone, which is why I brought up this observation and shared my solution with the scientists.
I didn't know about point #2. I thought the core had to be made up of mostly hydrophobics to be valid.
With respect to point #3, I started the puzzle by changing all residues from isoleucine to serine so that I could pack a tight core. I suspect I packed it too tightly, which is why, after a global mutate, I still have over a half dozen serines and threonines buried inside the core.
I had mentioned to him after his response, that I believe most of the community is not aware of that fact about #2! As I'd brought up the question once, wondering why it was that my Cores were including Phillics, and most were just as perplexed as I. All that could be speculated was that they were providing protection for the actual "Core" (Phobics) and it therefore was deemed "required" to keep the Core, in itself becoming a Core. lol
As for being packed too tight, I imagine that's it exactly!
#1 Yes, looking at your shared solution, I think this is a bug in the BUNS Objective, but will need to dig into it more.
#2 From a scientific view, you are absolutely right. The protein core must be hydrophobic. If the core is not hydrophobic, the protein will not fold. However, the Core Existence Objective in Foldit doesn't address the hydrophobicity of your core; the Objective only encourages you to design a compact overall shape. We rely on the score function (the Hiding subscore) to make sure that residues in the core are actually hydrophobic.
#3 Yes! This is a curious pitfall in protein design that wasn't really appreciated before Foldit players exposed it. Little details in the shape of the backbone (like too-close helices) can cause big problems in design. I don't think the score function is to blame (probably you would be able to get a higher score with a slightly expanded fold packed with bulkier hydrophobic sidechains). But it is really easy to get yourself in this position.
Date/Time: 2020-09-20 13:41:06.840 -0400
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