This is the thirteenth 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.
We have also removed two of the Core Exists Objectives to allow for diverse solutions including well-folded linkers that don't explicitly pack against the binders. We have also dropped the maximum residue count to 280.
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!
Residue Count (max +250)
Penalizes extra residues inserted beyond the starting 260, at a cost of 25 points per residue beyond 270. Players may use up to 280 residues in total.
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.
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Buried Unsats (max +500)
Penalizes polar atoms on the linker that cannot make hydrogen bonds, -60 points per atom.
