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1948: Designable Linker: Coronavirus Spike Binder
Status: Closed


Name: 1948: Designable Linker: Coronavirus Spike Binder
Status: Closed
Created: 01/27/2021
Points: 100
Expired: 02/03/2021 - 23:00
Difficulty: Intermediate
Description: This is the twelfth puzzle in the designable linker series! We are providing parts of two of the best-known designed binders to the SARS-CoV-2 spike, and are challenging players to link them together with a rigid linker! One of them is LCB3 which you have seen before, but the one without any adjoining spike is called AHB2, and is another de novo protein that is meant to mimic ACE2, which is the human protein that SARS-CoV-2 binds to when it infects your cells. The two helical bundles are the parts of the two binders. They are currently connected with a flexible alanine linker that needs to be redesigned.

We have also included the parts of the actual spike that are within 15 angstroms of the termini of the binders, so you know what regions your binder has to avoid to prevent clashing. The big thing for puzzles like these is to have buried hydrophobics at the interface between the linker and the binder helices to encourage structural rigidity. Packing the linker against the helices can help it maintain its shape. We are allowing for select residues on the binders to be fully designable to encourage hydrophobic packing.

Currently everything is frozen except for the linker and the sidechains of several residues that can pack nicely with any designed linker. The linker residues are completely designable. The two binder domains are held in place with strong constraints.

We have included a few objectives to help players generate well-folded designs. The major new one is the ContactMolecularSurfaceScore objective that was just released into Foldit. This is a combination of two different Rosetta metrics that are supposed to reward complexes where the linker has good shape complementary and low binding energy with respect to the binders. This should help keep the linker rigid. As we get more data on the proper threshold values, we hope that this will help binder design across a range of interfaces. We have capped the objective at your CMS + 700. It is a difficult problem to design a linker that can hold the binders in place. This type of puzzle is new for Foldit, and we are excited to see what players come up with! Good Luck!
Categories: Design, Overall

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neilpg628's picture
User offline. Last seen 4 days 20 hours ago. Offline
Joined: 08/01/2019
Groups: Foldit Staff

Residue Count (max +250)
Penalizes extra residues inserted beyond the starting 260, at a cost of 25 points per residue beyond 290. Players may use up to 300 residues in total.

Core Existence: AHB2 (max +2400)
Ensures that at least 34 percent of residues are buried in the core of the AHB2-linker unit.

Core Existence: LCB3 (max +2400)
Ensures that at least 34 percent of residues are buried in the core of the LCB3-linker unit.

Core Existence: Linker (max +2400)
Ensures that at least 35 percent of residues are buried in the core of the linker unit.

Interaction Energy (max +500)
Monitors that all large PHE, TYR, and TRP residues are scoring well.

SS Design (max +500)
Prohibits CYS residues. Penalizes GLY, ALA residues in sheets. Penalizes GLY, ALA, SER, THR in helices.

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.

ContactMolecularSurface (max +700)
Checks that the designed linker has an energetically favorable interface with the binders.

Buried Unsats (max +500)
Penalizes polar atoms on the linker that cannot make hydrogen bonds, -60 points per atom.

grogar7's picture
User offline. Last seen 28 min 56 sec ago. Offline
Joined: 10/03/2011
size unwieldy

Took 7:30 minutes to run one iteration of mutate tool

Joined: 12/07/2007
Groups: Contenders


Joined: 12/06/2008
Groups: Contenders
OMG, the LAG!

OMG, the lag! I try to do a simple pull and wiggle. It takes forty-five seconds to a minute to start it, and once it starts, it continues forty-five seconds to a minute to stop... which inevitably pulls it beyond where I want it.

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Developed by: UW Center for Game Science, UW Institute for Protein Design, Northeastern University, Vanderbilt University Meiler Lab, UC Davis
Supported by: DARPA, NSF, NIH, HHMI, Amazon, Microsoft, Adobe, RosettaCommons