The middlegame is perhaps the least defined and least well-understood part of FoldIt. Members of Another Hour Another Point tend to describe the middlegame as being all those actions you take after you've stopped looking back on the original configuration of a puzzle, but before you have begun making the minor, largely invisible adjustments found in the endgame.
Nudge plays a prominent role in the middlegame, as does Rebuild. Beyond that, look for Hydrophobicity, Compactness, and Aesthetics. Ask yourself continually if a protein "looks" right. And if it doesn't, consider making changes. The middlegame is a time for bold strategic decisions.