(1) I start by focusing on target bonds that are not forming (target helix pairs). I sometimes manually “flip” pairs or I will use the https://eternagame.org/web/script/9251108/ Arc Plot Interface (v2.0) booster to help with this, by locating and mutating target pairs that are not forming in the MFE/natural shape. I look for mutations that both reduce the red areas and lower the delta Free Energy. I look for one of the “best” pair mutations that (a) reduces existing mismatches, (b) does not seem to introduce any significant new mismatches, and © reduces the delta Free Energy. I sometimes stop with a “#stem” design that only mutates target helix pairs.
If I cannot progress after a while, I may also progress to (2) looking at target loop bases that are mismatched in the natural form. I then try mutations of these bases to break the mismatch pairs. The same criteria apply: mutations that (a) reduce existing mismatches, (b) do not seem to introduce any significant new mismatches, and © reduce the delta Free Energy.
I will also start from existing designs by other players, try undoing loop base mods, or mods that make minimal/no dFE gains, and then add mods of my own.