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2180: Symmetric Terbium Binder Design

Closed since 2 months ago

Intermediate Overall Design Symmetry

Summary


Created
July 29, 2022
Expires
Max points
100
Description

Design a symmetric trimer around a terbium binding site! Terbium is an element in the lanthanide series of the periodic table. Because of their unique magnetic properties, lanthanides like terbium are useful for MRI medical imaging. We'd like to design a protein that can bind lanthanide ions for enhanced MRI imaging. Terbium can be be bound with 3-fold symmetry, so a protein trimer could be the perfect binder!



The starting structure includes a terbium binding site from a previously designed coiled coil protein. The binding helices are held in place with strong constraints, as are the sidechains that bind the terbium ion. However, the rest of the protein needs to be folded and redesigned so that the three symmetric copies will assemble correctly. The monomer subunit should have a strong core of hydrophobic residues. Compared to the original coiled coil, we think this can give us increased folding stability and better binding.



This puzzle enables AlphaFold predictions for the monomer subunit of your design, so you can upload your solution for AlphaFold using the AlphaFold prediction tool. AlphaFold will predict the structure of your monomer subunit only (i.e. in the unbound state, in the absence of other symmetric copies). If you load this prediction, then Foldit will attempt to align the prediction with your solution. If you continue working off of the AlphaFold prediction, you may need to make adjustments at the interface where the monomer subunit interacts with symmetric copies. The Buried Unsats Objective will incur a penalty for buried polar atoms that can't make H-bonds. See the puzzle comments for Objective details.

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Comments


bkoep Staff Lv 1

Buried Unsats (max +500)
Penalizes polar atoms that cannot make hydrogen bonds, -150 points per atom (not including symmetric copies).

Core Existence: Monomer (max +1700)
Ensures that at least 17 residues are buried in the core of the monomer unit.

Core: Complex (max +0)
Awards no bonuses or penalties.

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

SS Design (max +500)
Penalizes all CYS residues.

Neural Net (max +0)
Achieve an AlphaFold prediction confidence of 80% or more.

LociOiling Lv 1

Ligand fans will be disappointed to learn that terbium was unable to appear in this puzzle due to a scheduling conflict.

Instead, there's a terbium-size hole in there somewhere.

Terbium will be green-screened in during post-production.

HuubR Lv 1

In this puzzle, the Insert and Delete Segment actions are enabled, depending on the selected segment(s).

Tried to use these actions:

  • Insert "cannot insert any more" (unless I tell it to insert zero segments, but that is not very useful). That makes sense: I cannot use more than the given 65 segments.
  • So I have to use Delete first?  The first and last segments are not deletable, nor are the segments near the binding site, and when I select any other segment (one or more), Delete causes an immediate crash.</ul> As a result, this puzzle is restricted to having the binding site in the exact centre of a 65 residue chain. I would say that is an unnecessary and unwanted restriction, but maybe someone can explain the reason?

bkoep Staff Lv 1

Thanks for the feedback! I'm able to reproduce the crash here, but it's unlikely we'll have a fix ready before the puzzle expires.

Practically speaking, this unfortunately means that the binding site is fixed in the center of the chain for this puzzle. We'll try to get this fixed so we can do another round in the future!