Understanding the effect of spatial confinement on protein folding is directly relevant to biological processes such as folding in a chaperonin cavity or in a ribosome tunnel. In addition, macromolecular "crowding" effects in the cellular environment can significantly alter folding from what is observed in vitro. In certain limits, the protein behavior in such a crowded environment can be equivalently modeled as protein localization in an effective confining boundary. Although several previous studies have provided important insights into this problem, there is no clear agreement on the scaling of folding thermodynamics with cavity size and very little is known about the folding kinetics with regard to such scaling expectations.

We will present results using coarse grained models for two proteins, a three-helix bundle (prb7_53) and protein G, as a function of the geometry and size of the confining potential. From long equilibrium simulations (~ 15 microseconds each) over a range of temperatures, we characterize the thermodynamics and kinetics of folding at each confinement condition and in the bulk. Remarkably, we find that the effect of confinement on folding thermodynamics (stabilization of folded state) for both the proteins closely follows the scaling behavior expected from polymer physics, because the dominant effect of confinement is on the unfolded state which behaves like a random excluded volume chain. We also find that the acceleration in folding kinetics obeys a similar scaling, although small deviations are observed, mainly resulting from transition state confinement. A secondary effect on protein dynamics is the confinement-induced change in local diffusion coefficients, most notably near the unfolded state basin. However, we do not find any net slowdown in the folding rate even for very small confining cavities.