Macromolecular Crowding Effects on Pressure-Induced Protein Folding/Unfolding

In the interior of a cell, protein folding occurs in a highly crowded environment. It is still unclear how excluded volume from macromolecules affects folding/unfolding transitions. To gather local features of the folding landscape, we use high hydrostatic pressure to unfold the protein in our coarse-grained simulation. Pressure perturbs the protein heterogeneously, which greatly facilitates characterization of the folding mechanisms. Our model uses a mean field approach to account for pressure by adjusting the parameters describing the native stabilizing interactions and the desolvation barrier. Macromolecular crowding agents were modeled as hard spheres to mimic the cell-like environment. We provide theoretical incite into the mechanism of pressure-denaturation in highly crowded conditions, and show water gradually penetrating the hydrophobic core over a wide range of pressures. Furthermore, this study takes us one step closer in understanding the ultimate goal of protein folding in vivo. This research was funded by the National Science Foundation, MCB-1412532, PHY-1427654 and ACI-1531814.