Protein folding under confinement: a role for solvent.

D. Lucent, V. Vishal, V. S. Pande. Proceedings of the National Academy of Sciences (2007)

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SUMMARY: When proteins fold inside a cell, they are frequently subjected to various amounts of spatial confinement. Specifically, misfolded or unfolded proteins can be encapsulated inside a helper molecule called a chaperonin. These chaperonins are involved with helping proteins fold inside cells. Here we investigate how confinement affects protein folding using a simple model: a fast folding mini-protein confined to a nanopore. We find that if we confine the protein, but allow the surrounding water molecules to pass freely in and out of the nanopore, the protein is more likely to reach the folded state. On the other hand, if we make the nanopore water-tight, we find that the protein is less likely to fold. Specifically it is pushed into a small non-native globule. This suggests that when thinking of folding inside a confined space (like a chaperonin) it is important to remember both protein and water are confined, and this confined water can have an affect on protein folding.

ABSTRACT: Although most experimental and theoretical studies of protein folding involve proteins in vitro, the effects of spatial confinement may complicate protein folding in vivo. In this study, we examine the folding dynamics of villin (a small fast folding protein) with explicit solvent confined to an inert nanopore. We have calculated the probability of folding before unfolding (P fold) under various confinement regimes. Using P fold correlation techniques, we observed two competing effects. Confining protein alone promotes folding by destabilizing the unfolded state. In contrast, confining both protein and solvent gives rise to a solvent-mediated effect that destabilizes the native state. When both protein and solvent are confined we see unfolding to a compact unfolded state different from the unfolded state seen in bulk. Thus, we demonstrate that the confinement of solvent has a significant impact on protein kinetics and thermodynamics. We conclude with a discussion of the implications of these results for folding in confined environments such as the chaperonin cavity in vivo.