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1915: Designable Linker: Coronavirus Spike Binder

Closed since almost 2 years ago

Intermediate Overall Design


November 11, 2020
Max points

This is the second 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 20 angstroms of the termini of the helices on the binders, so you know what regions your binder has to avoid to prevent clashing. The designable helices are a possible starting point for your linker designs.

Currently everything is frozen except for the linker and a portion of the helix on each binder. These residues are designable, and only residues on the linker and helices can be added and deleted. The two binder domains are held in place with strong constraints.

We have included a few objectives to help players generate well-folded designs. There are also some important differences between this and the first designable linker puzzle.

  1. The BUNS Filter is removed.

  2. The VAL helices are now treated like the linker, in that they are unconstrained, mutable, deletable and designable.

  3. The PDB is slightly different, and has much less clashing between residues on the spike and the binder.

  4. Because some spike residues are missing, the max linker length is slightly longer, since certain spike residues are no longer present.

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!

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neilpg628 Staff Lv 1

Residue Count (max +550)
Penalizes extra residues inserted beyond the starting 205, at a cost of 55 points per residue. Players may use up to 215 residues in total.

Core Existence (max +2400)
Ensures that at least 28 percent of residues are buried in the core of the monomer unit.

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

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

BootsMcGraw Lv 1

What was the reason for removing the BUNS filter? I thought a minimum number of BUNS was necessary for good core formation and a stable structure.

Mike Cassidy Lv 1

MikeCassidyToday at 12:11 PM
Clicking on the Puzzle name in the App window is not opening up the puzzle in my www browser

neilpg628 Staff Lv 1

BUNS are more of an issue when designing interfaces between binders, because polar atoms are required at the interface to solubilize the monomers, but these polars need to make HBonds in the bound state. In this case, all buried atoms can be nonpolar since we only want the linker to fold. We have no bound and unbound states.

spvincent Lv 1

Wiggle is acting very strange on this pose (Linux/main). The score initially increases but then decreases to a value below the original. Seems unrelated to filters or wiggle power. Scientist-shared the offending pose as "bad wiggle 34896"

bkoep Staff Lv 1

This looks related to Building Blocks that have been inserted into the Blueprint panel.

The Building Blocks add torsional constraints that try to push the backbone toward ideal phi/psi torsions. This helps to promote backbone patterns that are common in known protein structures, but these constraints (like rubber bands) can cause loss of points during Wiggle.

bkoep Staff Lv 1

Yes, that's a problem that was never meant to persist. We had always planned to create a visual representation that shows Building Blocks on your solution, but it keeps getting pushed down the to-do list.