Scaling Laws for Protein Folding under Confinement

Spatial confinement significantly affects protein folding. Without the confinement provided by chaperones, many proteins cannot fold correctly. However, the quantitative effect of confinement on protein folding remains elusive. In this study, we observed scaling laws between the variation in folding transition temperature and the size of confinement, (<i>T</i>_f - <i>T</i>_f^bulk)/<i>T</i>_f^bulk ∼ <i>L</i>^-<i>ν</i>. The scaling exponent <i>v</i> is significantly influenced by both the protein's topology and folding cooperativity. Specifically, for a given protein, <i>v</i> can decrease as the folding cooperativity of the model increases, primarily due to the heightened sensitivity of the unfolded state energy to changes in cage size. For proteins with diverse topologies, variations in topological complexity influence scaling exponents in multiple ways. Notably, <i>v</i> exhibits a clear positive correlation with contact order and the proportion of nonlocal contacts, as this complexity significantly enhances the sensitivity of entropy loss in the unfolded state. Furthermore, we developed a novel scaling argument yielding 5/3 ≤ ν ≤ 10/3, consistent with the simulation results.