The Energy Hill
I like to think of folding as being like a ball rolling down a hill. The further down the hill, the lower the energy state of the ball and the higher the score. The hill, however, has some dips in it. When the ball is in one of the dips, you are in a local minimum. The only way to get out of a local minimum is to first get the ball to a higher energy state, then get it rolling downhill again. How much energy you need to apply to get over the lip of the dip depends on how deep the dip is. The depth is the amount of mojo the protein has.
Opening Moves[]
At the start of the puzzle, you will likely be acquiring points at a steady pace for a while until you get into one of these local minimums. Several other people have given good tips on how to approach the start of the puzzle. I have a few things to add, that have been added to foldit since most of those were written.
I generally use the alignment tool to find an initial position. I may also do partial threading.
If the puzzle is multi-start, I will try each of them. I use the [tlaloc select multi-start] recipe to find each of the starts, then wiggle and shake them out to find which has the best starting score.
Middle Game[]
The trick in the middle game is to get out of local minimums. You need to find ways that move to a lower energy state, then see if you are over the lip. There are a number of ways to make that happen.
Clashing. My favorite clashing script is a variation on the bluefuze script, [tlaloc repeat bluefuze].
Banding. I have various scripts that play with banding. [tlaloc contract] and [tlaloc cataclysm] work well.
End Game[]
The goal is to eke out every fraction of a point. Others have written this up, well. My favorite script here is [tlaloc repeat settle].
Technique for Matching a Guide[]
While you are doing this, your score will likely go very negative. Don't worry. It should get better later.
- View the options, turn on "Show Outline," set the background color to white, and view stubs on the sidechains, view the guide, and set color relative to guide. Turn all the other view options off.
- If threading is available, thread the entire protein.
- Use tlaloc hydrophobe to stabilize the structure.
- Use tlaloc repeat settle to get the protein into a good backbone position. You may then use additional techniques that help the backbone position itself.
- Click Align Guide. Don't ever do that again during the rest of the process or you will have to start over.
- Start at segment 1 of the protein. You can hover over a segment and hit tab to see what segment number you are dealing with. Close that window when done with it, though, because it vastly slows down the interface.
- Starting at segment 1 of the protein, hover the mouse over the sidechain. It should show the corresponding sidechain in the guide.
- If the segment is not the same secondary structure as the guide, modify it so that it matches the guide: Sheets, Loops, and Helixes.
- Drag a band from the first segment of the real sidechain to the first segment of the sidechain in the guide. You will need to turn the protein at 90 degree angles several times to get it to be positioned correctly in 3D, since you are working in 2D. Hold down the 'alt' key to keep the band from snapping to some other item in the protein.
- Wiggle All until it is stable. Shake sidechains.
- Run the tlaloc Band Strength to 10 script.
- Wiggle All until it is stable. Shake sidechains.
- Run the tlaloc Band Strength to 1.0 script.
- Wiggle All until it is stable. Shake sidechains.
- Move on to the next segment. Every 10 segments do this process.
- Run the tlaloc Band Strength to 0.1 script.
- Wiggle All until it is stable. Shake sidechains.
- Run the tlaloc Band Strength to 1.0 script.
- Wiggle All until it is stable. Shake sidechains.
- Repeat the process until you have the entire protein done.
- Run tlaloc Repeat Settle.
- Disable bands. Wiggle and shake to allow the backbone to find its natural shape.
- Run tlaloc Repeat Settle again.
- Re-enable bands. Wiggle and shake.
- Now proceed to rebuild the entire protein in short segments until the protein matches the guide exactly.
Tlaloc's Laws of Folding[]
Tlaloc's Law of Scripts[]
Just as you hover the mouse over the Cancel button to stop the script, it will find points.
Corollary #1: Hovering the mouse over the button to find points doesn't work.
Corollary #2: It will only find the smallest number of points necessary to keep you from canceling the script.
Tlaloc's Law of Scoring[]
If you spend hours trying to find the 1 point you need to rank the person above you, someone new will come out of the blue and pass you both by 50.
Video[]
This is the video that UW|360 did of me and my family back in 2009 talking about foldit: