Pathways for folding and re-unfolding transitions in denatured conformations of anhydrous proteins

Using molecular dynamics simulations, we explore the mechanism that may underlie the type of folding transitions observed experimentally in anhydrous proteins. Recent relaxation studies of a partly unfolded α-helical bundle suggest an approach to simulating cycles of folding/re-unfolding transitions. Here, we provide evidence that such processes may be general, by uncovering a similar relaxation pattern in lysozyme, a more flexible α/β protein. We find that, while refolding is initiated by partial polymer collapse, the reversible re-unfolding of compact nonnative structures proceeds as a correlated transition not unlike the direct unfolding of lysozyme from its native state.