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1873: Symmetric Trimer Design: Limited Interface

Closed since about 2 years ago

Intermediate Overall Design Symmetry


August 05, 2020
Max points

Design a symmetric protein trimer, with 3 identical chains that assemble together! This puzzle has no H-Bond Network objective, but there is "Core Limit: Complex" objective meant to limit the size of the interface between symmetric chains. An interface that is too large, with too many orange hydrophobics, can prevent the individual subunits from folding properly. The "Core Limit: Complex" objective will incur penalties if there are too many buried residues in the total assembly. This puzzle uses the Buried Unsats Objective, with a large penalty for buried polar atoms that can't make H-bonds. See the puzzle comments for more Objective details.

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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 +1600)
Ensures that at least 16 residues are buried in the core of the monomer unit.

Core Limit: Complex (max +500)
Checks that no more than 60 residues are buried in the symmetric complex, including the interface between monomer units.

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

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.

BootsMcGraw Lv 1

One would think that having disulfide bridges would help stabilize and strengthen the three-dimensional structure of a designed protein.

You've explained before why (for the moment) no alanines in helices. But why no cysteines at all?

bkoep Staff Lv 1

You're right, a disulfide bridge within a single subunit might help to stabilize the folding of the subunit. But it could also confound folding by forming off-target bridges if the protein is prone to misfolding – either within the subunit or between two separate copies of the subunit.

For this reason we tend to prefer disulfides for stabilizing proteins that can already fold up on their own (without disulfides), but only do so with marginal stability. Oddly, very few de novo protein designs fall into this category. Typically, a de novo design folds up and is very stable (so we don't need disulfides); or it fails to fold at all (so cysteines are likely to form off-target disulfides).

Cysteines also complicate the experiments we use for testing designs in the lab, if some designs require disulfide-forming conditions and others do not.

A final practical concern is that, if we wanted to design disulfide bridges into our proteins, we would like some way (an Objective) to discourage unpaired cysteines in the design. Foldit doesn't have a problem modeling disulfides and unpaired cysteines in the same design, but if we test this protein in disulfide-forming conditions, those unpaired cysteines will find some way to form a disulfide.