puzzle picture
1979: TGF Receptor Binder Design: Round 1
Status: Closed

Summary

Name: 1979: TGF Receptor Binder Design: Round 1
Status: Closed
Created: 04/09/2021
Points: 100
Expired: 04/16/2021 - 23:00
Difficulty: Intermediate
Description: Design a protein that can bind to the TGF-beta receptor! TGF-beta is a human signaling molecule that cells use to communicate with one another. In some circumstances TGF-beta inhibits the immune response, and is important for regulating over-active immune cells if they risk damaging normal human tissue. However, certain types of tumors release extra TGF-beta to deceive the immune system so that the tumors can grow unchecked. We'd like to design a protein binder that can stick to the TGF-beta receptor and prevent this deceptive signaling. A successful binder could be part of a selective cancer treatment that helps the natural immune system fight tumor growth.

In this puzzle, we've presented a section of the target receptor that normally binds TGF-beta. The backbone and most of the sidechains are frozen, except at the binding site, where flexible sidechains are shown in color. Players can design a new protein that can bind to these sidechains and block TGF-beta. In order to bind the target receptor, designs will need to make lots of hydrophobic contacts and satisfy any polar atoms that are buried at the interface. But designs will also need to have lots of secondary structure (helices or sheets) and a large core, so that they fold up correctly! We know from prior experiments that this is an exceptionally difficult binding target, so the Contact Surface Objective is more stringent, and will not max out until you reach Contact Surface > 500. See the puzzle comments for Objective details.
Categories: Design, Overall

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bkoep's picture
User offline. Last seen 1 day 6 hours ago. Offline
Joined: 11/15/2012
Groups: Foldit Staff
Objectives

DDG Metric (max +2000)
The predicted binding energy of your design. The goal DDG is -40.0 or less.

Contact Surface Metric (max +2000)
Measures how much of your binder surface is in close contact with the target protein. The goal Contact Surface is 500 or more.

Buried Unsats (max +500)
Penalizes 100 points for each polar atom that cannot make any hydrogen bonds.

Core Existence (max +1500)
Ensures that at least 25 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.

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.

SS Design (max +500)
Disabled use of CYS residues. Penalizes GLY, ALA residues in sheets and helices.

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Developed by: UW Center for Game Science, UW Institute for Protein Design, Northeastern University, Vanderbilt University Meiler Lab, UC Davis
Supported by: DARPA, NSF, NIH, HHMI, Amazon, Microsoft, Adobe, Boehringer Ingelheim, RosettaCommons