Confinement and Protein-Wall Interactions Can Significantly Alter Protein Folding Landscape

Protein folding in the cell occurs in a crowded, heterogeneous environment, a perturbation that may alter both the thermodynamics and kinetics of folding relative to observations made in dilute solutions. In several situations of interest, macromolecular crowding effects can be approximated by confinement. These confinement effects may arise naturally in a cell when the proteins are localized in a small volume such as exiting from a ribosome tunnel or confined in a chaperonin cavity. Previous studies have mostly focused on confinement effects due to encapsulation in repulsive cavities (spherical, cylinderical, or planar) in the absence of explicit solvent. 

To address the role of confinement - specifically attractive protein-wall interactions, on protein folding, we have performed large-scale folding simulations using an all-atom explicit solvent model. We find that the folding free energy landscape of a beta-hairpin is significantly modulated in the presence of attractive confinement. Different propensities of hydrophilic versus hydrophobic side-chain atoms towards confining walls leads to the disappearance of a misfolded state populated in bulk having hydrophobic side-chains oriented on opposite sides of the hairpin. We discuss the implications of these results for protein folding mechanism in a chaperonin cavity.