1609: CR2 Binder Design

Closed since about 7 years ago

Summary

• Created: December 12, 2018
• Expires: December 20, 2018 at 23:00 UTC
• Max points: 100

Description

Design a protein to stabilize the CR2-binding helices! Complement receptor 2 (CR2) is a protein found on the surface of human B-cells, which respond to viruses and other pathogens found in the body. When the CR2 protein is activated, these immune cells become especially sensitive. We want to design a protein that can bind to CR2 and help trigger a strong immune response. Such a protein could boost the effectiveness of vaccines. The starting structure contains two helices from a natural protein, which is known to bind CR2 but is not very stable. We're asking Foldit players to design a protein to stabilize these two helices in their starting orientation. The side chains involved in CR2 binding are frozen; Foldit players should avoid building around these residues, which need to remain accessible for CR2 binding. Some protein design Objectives are in effect; see the puzzle comments for details.

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Comments

[bkoep]

Residue IE Score (max +500)
Monitors that all PHE, TYR, and TRP residues are scoring well.

Core Exists (max +500)
Ensures at least 30% of residues are buried in the core of the protein.

SS Design (max +500 +300)
Penalizes all CYS residues. Penalizes GLY, ALA residues in sheets. Penalizes GLY, ALA, SER, THR in helices.

Residue Count (max +500)
Penalizes extra residues inserted beyond the starting 100, at a cost of 25 points per residue. Players may use up to 110 residues in total.

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.

[Mike Cassidy]

I can change them to sheets, at least some of the segs. That isn't correct right?

[Mike Cassidy]

I can't change four side chains that are giving me penalties.

Seg 5 Glycine
Seg 6 Serine
Seg 16 Alanine
Seg 89 Glycine

[bkoep]

You should not be able to move the backbone of the helices at all.

You may be able to assign some segments to sheets (e.g. in Structure Mode), and they will be displayed as twisted, crimped sheets. But you will not be able to use Idealize SS to straighten them into proper sheets. They should remain coiled as a helix, regardless of the secondary structure assignment you give them.

If you're able to actually move the backbone of the helices, can you please share your solution with scientists?

[bkoep]

That's right. These residues, which we normally don't like in helices, are important for binding CR2, so we don't want to change them.

So, the true max bonus for the SS Design Objective is only +300 (I've fixed this in the Objectives comment above).

[Mike Cassidy]

Is it possible to get Ideal Loops at the connection between the two given helices and the section we are building?

[Susume]

If you give us another like this one, please let us delete residues to fall a little below the given number. As it is, I can only delete to shorten a loop if I add residues somewhere else first. The least I could add would be 4 (a whole turn of helix, or extending a sheet pair by 2 each), and adding four to delete one is costly.

[Susume]

I discovered the residue next to the cut can't be deleted but the one next to that can - so we can go below the given number.