Design a protein that can bind to the monkeypox H3 target! The Neural Net Objective awards a 2000 pt. bonus for AlphaFold predictions with both high confidence and high similarity to the current solution. After an AlphaFold prediction is complete, load the original or predicted structure from the AlphaFold panel to receive the bonus. You can continue to work on this solution, but the bonus will disappear if the similarity drops. Note that the table in the AlphaFold panel only displays the similarity of the original solution; the true similarity of your current solution is recalculated by the Neural Net Objective as you change its structure.
Once you've designed a binder for the target, upload your solution for AlphaFold using the AlphaFold prediction tool. AlphaFold will predict the structure of your binder chain only (i.e. in the unbound state, in the absence of the target). If you load this prediction, then Foldit will attempt to align the prediction with your solution (i.e. in the bound state, making an interface with the target). If you continue working off of the AlphaFold prediction, you may need to make adjustments at the interface where the binder interacts with the target.
The monkeypox H3 protein is displayed on the surface of the virus. The complete role of H3 is still unclear, but it seems to be involved in the recognition of human cells. A binder for H3 could be useful for detecting monkeypox, and might even help to block infection. Scientists have yet to solve the structure of the monkeypox H3 protein, although we do have a crystal structure of a related protein from Vaccinia virus. The structure of the target in this puzzle comes from an AlphaFold prediction of monkeypox H3.
In this puzzle, we've presented a portion of the H3 target with several exposed hydrophobic residues, which we think will be good for binding. 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 on the target. In order to bind the target, 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! See the puzzle comments for Objective details.
DDG Metric (max +2000)
The predicted binding energy of your design. The goal DDG is -40.0 or less.
Contact Surface (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 20 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.
Neural Net (max +2000)
Achieve an AlphaFold prediction confidence of 80% or more, and similarity to current solution is 80% or more.
Protein we create often touch those segments : 3, 5,6, 30, and 58. Maybe it can be interesting to have them movable ? And maybe, 46-asparatate should be not movable ?
Other question : Sometimes, moving sidechain in target, like 61-tyrosine, can give more points at puzzle end (by resolving some constraints, like avoid a BUN, ect), but I want to be sure it is not a problem in lab. Maybe some rotamers should not be allowed if we are sure they can add problem ?
