Core filter
"As you know, a protein is made up of a long chain of amino acids, but the chain folds up into a globular, compact shape. One of the main forces that drives folding is the burial of hydrophobic residues. Since the protein is surrounded by water, the only way to hide the hydrophobic residues is to fold them into the center of the protein and shield them from water with polar residues. This is why the most stable proteins have well-packed cores with lots of buried hydrophobics.
When designing a protein, we want to make sure that it has a well-packed core of hydrophobic residues to stabilize the fold. The "Core Exists" filter calculates the solvent-accessible surface area of each residue to determine which residues are buried and which residues are exposed to water. Then it checks that the number of buried residues meets some threshold (usually 30% of the total number of residues). Additional buried residues get a score bonus, but any fewer than the threshold and your protein will get a penalty. If a protein does not pass the filter, the Show checkbox will highlight residues that are not buried—you should try to pack more of these into the core of your protein.
Note that, in puzzles with multiple chains, residues at the interface between chains are counted as buried. So, while individual chains should have their own cores, large well-packed interfaces will also contribute to the filter score."[1]
An additional note on multiple-chain puzzles:
"Strive for designs that have individual cores.
There are cases in nature in which the subunits of a multimer do not have individual cores (tropomyosin in muscle, for example, is a dimer that consists simply of two helices wound together). Such structures can be stable, and may even get you a lot of points in a design puzzle. But these kinds of designs don't exploit the full potential of protein interface design, and they're not very interesting.
At the Baker lab, we get really excited about designs that have individual cores as well as strong interfaces. These structures receive lots of attention and are more likely to enter our pipeline of analysis and testing. A good example of this would be MurloW's scientist-shared solution from Puzzle 691, which was used as the starting point for Puzzle 725."[2]
And a note on mutation:
"For the most part, mutating a residue will not affect how that residue contributes to the Core Exists filter. The residue will remain as "core" or "surface" and your Core Exists status will not change.
However, there are occasional cases where a mutation drastically changes the solvent-accessible surface area of the residue, and the mutation will affect the filter. Mutate All is *not* aware of the filter, and it will sometimes make mutations that cause the filter to fail. If you're having trouble meeting the Core Exists filter requirement, you could try hand-mutating residues that look like they are in the core but are still highlighted by the filter.
Note that the Core Exists filter does not care whether your core residues are hydrophobic or polar. You can have a core full of polar residues and the filter will still pass, although your overall score will drop. Once you have a core, Mutate All is pretty good about mutating those residues to hydrophobics."[3]
Layer filter
The "Layer Design" filter looks at the interactions of the residues based on the surface area of the protein. Residues can be either in the core, on the boundary or on the surface of the protein. Depending on the surroundings, the "Layer Design" filter will give you a bonus if your amino acid matches what it was expecting.
IE filter
the Residue IE Score monitors that all PHY, TYR, and TRP residues are scoring well.
"The Residue interaction energy bonus is a comparison of the residues in your protein versus those of a large set of native proteins.
We take a subset of score terms that have to do with residue-to-residue interactions and give each residue a combined score. We see how well your amino acid stacks up against others of the same type in the set of native proteins we scored. We do this across the entire protein and determine a bonus or penalty.
This will give penalties when residues are not contributing at a proper level. In essence, is this residue pulling its weight based on what we have seen it capable of doing on average."[4]
"The main purpose is to prevent unrealistic residue substitution in Foldit. For example, it makes adding tryptophans, tyrosines, and phenylalanines on the surface of a protein score poorly. Putting hydrophobic residues on the surface is bad because it makes the protein very "sticky", likely to interact with many other proteins, including itself, and hence not very useful."[5]
Another way of wording this explanation: "Natural proteins avoid putting Tryptophan, Phenylalanine, and Tyrosine on the surface. However, Foldit often gives a score bonus if you load up the surface of your design with Tryptophan. The Residue Interaction Energy filter helps to counteract that, helping you make better designs."[6]
The fast way to pass this filter is to mutate all phy, tyr and trp to other sidechains.