This is the eighth 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! 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. We now have three Core Exists Objectives in the same puzzle. One is for incentivizing hydrophobic interactions between the LCB1 binder and the linker and one is for hydrophobic interactions between LCB3 and the linker. The third is active on the linker alone. The hope is that this way linker designs pack against the binder helices for rigidity while still making sure that the linker is well folded. The difference from the previous puzzle is that the residue count filter has become less strict to encourage the use of more residues if necessary.
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 240, at a cost of 25 points per residue beyond 250. Players may use up to 260 residues in total.
Core Existence: LCB1 (max +2400)
Ensures that at least 34 percent of residues are buried in the core of the LCB1-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 LCB3-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.
