Hello! I am Donuts554. Here I am going to share some of the strategies I use when playing Foldit.
To me, overall, when I protein fold, I try to take into consideration each and every amino acid so that they all have their own true say in the protein's tertiary structure. Currently, I think and wonder that just generalizing parts of the structure of the protein into secondary structures and then aligning the secondary structures is unrealistic. It is because I don't think Amino Acid residues can instantly curl up into an organized secondary structure, including loops. However, I do use the Idealize SS tool in some of my strategies. Currently, I think that the string of amino acids gradually curls up into shape, overcoming sorts of energy barriers along the way.
This means I also follow the general rule, orange-colored hydrophobic amino acids are inside the protein, and blue-colored hydrophilic amino acids are outside the protein. Of course this is prevalent in most proteins, with a hydrophobic inside with a hydrophilic crust, except for membrane proteins, which have to be stuck in the membrane. In order for those membrane proteins to be stuck in the membrane, you have to have exposed hydrophobic Amino Acids sticking out. However, in the Foldit client as of 07/04/2020, exposed hydrophobic amino acid residues contribute to a low score in the protein. This is one of the imperfections in the Foldit scoring system, that have to be worked around.
Amino-Alternation Strategy Edit
My Amino-Alternation strategy is where the secondary structures are determined by the alternation pattern of the hydrophobic and hydrophilic amino acids from designated sections of the amino acid sequence, and then making the secondary structures themselves through the Idealize SS tool, and then aligned so that the hydrophobic sides of the secondary structures are on the inside, and so that the hydrophilic sides of the secondary structures are on the outside.
The reason I follow this current strategy for now is that I think that this proteins form secondary structures according to the alternation pattern of hydrophobic and hydrophilic amino acids on the amino acid sequence.
Determining the Secondary, by Examining the Primary Edit
When deciding on what parts of the amino acid sequence are the "secondary structures", the alternation pattern for at least 3 consecutive residues of hydrophilic amino acids to hydrophobic amino acids for different sections of the primary structure is determined. The alternation pattern can be 1:1, like an alternating pattern of orange and blue in the "Hydro" view option, or 2:1 or 2:2, like an alternating pattern of 2 blue and one/two orange residues.
Then if the alternation pattern is 1:1, I determine the SS to be a sheet, because there is about an even amount of the hydrophobic amino acids on the inside, and the amount of the hydrophilic amino acids to the outside of the sheet.
If the alternation pattern is 2:1 or 2:2, the secondary structure is determined to be a helix, because each full cycle of the helix is about 3-4 residues long, and so that there should be about an even amount of hydrophobic amino acids on the inside, and the amount of the hydrophilic amino acids to the outside of the helix.
If the alternation pattern for at least 3 consecutive residues is not 1:1 or 2:1 or 2:2, then the secondary structure is determined to be a loop.
After determining the secondary structures of all of the distinguished sections that are outlined in Structure Mode, I then use the Idealize SS tool to form the respective secondary structures on those designated respective sections.
Forming the Tertiary, by Aligning the Secondary Edit
To form the tertiary structure, I start with the closest secondary structure that is not loop towards the N-terminus, and then band the hydrophobic sides of each consecutive secondary structure that is not a loop together. After that, I use the Wiggle tool to bring those secondary structures together. I repeat this process for each pair of secondary structures, pair by pair.After all of the secondary structures are pulled together after using Wiggle to bring together the last pair of secondary structures that are not loop, I then remove all of the bands and then I use the Wiggle tool on the Auto Wiggle Power setting. I do this to have the secondary structures in the protein aligned more "naturally" through the Wiggle tool's preference.
If the protein doesn't look that good with not much green and a bit too much orange, then basically the process is repeated, but this time the known secondary structures are worked with first, and then modified.
It seems that the helical structures fold in more unstable regions to fold into a more stable structure with more angled turns and folds, and the sheets are found in more stable regions with less angled turns and folds, but stuck to each other to satisfy their backbone hydrogen bonds.
When I Use this Strategy Edit
So far as of now, I would use this strategy in the CASP-14 competition and in Prediction puzzles where the sequence can not be mutated but the structure can be changed.
Hydrophobic-Selective Strategy Edit
The Hydrophobic-Selective Strategy is where I band each consecutive pair of hydrophobic amino acids, from the N-terminus to the C-terminus.
The reason I sometimes follow this strategy is because it seems to model how proteins fold, one by one, due to the presence of hydrophobic amino acids along the amino acid sequence.