Salt-induced detour through compact regions of the protein folding landscape

In several cases, inorganic salts have been used to induce partly structured states in protein folding. But what is the nature of these states: Do they represent key stepping stones in the folding process, or are they circumstantial pitfalls in the energy landscape? Here we report that, in the case of the two-state protein S6, the salt-induced collapsed state is off the usual folding routes in the sense that it is prematurely collapsed and slows down folding by several orders of magnitude. Although this species is over-compact, it is not a dead-end trap but may fold by alternative channels to the native state.