  Using a structure-based coarse-grained model of proteins, we study the
mechanism of unfolding of knotted proteins through heating. We find that the
dominant mechanisms of unfolding depend on the temperature applied and are
generally distinct from those identified for folding at its optimal
temperature. In particular, for shallowly knotted proteins, folding usually
involves formation of two loops whereas unfolding through high-temperature
heating is dominated by untying of single loops. Untying the knots is found to
generally precede unfolding unless the protein is deeply knotted and the
heating temperature exceeds a threshold value. We then use a phenomenological
model of the air-water interface to show that such an interface can untie
shallow knots, but it can also make knots in proteins that are natively
unknotted.
