Protein model exhibiting three folding transitions

We explain the physical basis of a very simple hierarchical model for small globular proteins with water interactions. The water is supposed to accesses the protein interior in an “all-or-none” manner during the unfolding of the protein chain. As a consequence of this mechanism (somewhat speculative), the model exhibits fundamental aspects of protein thermodynamics, as cold and warm unfolding of the polypeptide chain. Decreasing the temperature below the cold unfolding the protein folds again. Accordingly, the heat capacity has three characteristic peaks. The cold and warm unfolding has a sharpness close to a two-state system, while the cold folding yields a less sharp transition. Interestingly, the entropy of the protein chain drives both the cold folding and the warm unfolding.