Coupled folding equilibrium describing the shift toward denatured material upon interaction with the cellular interior, as formalized in Eqs. 3–5. Coupled folding equilibrium describing the shift toward denatured material upon interaction with the cellular interior, as formalized in Eqs. 3–5. Both the denatured (D) and folded (N) species interact with the cellular molecules (m), but the interactions are stronger/more numerous for the structurally expanded and flexible D species. The increased heat capacity of unfolding (ΔCp) observed in the cellular compartment (Eqs. 1 and 2 and Fig. 2) is attributed to increased solvent-accessible surface area (dotted boundary) of the denatured ensemble (D cell), promoted by the transient association with neighboring macromolecules (m). Following Elcock’s estimate (44), SOD1I35A would at all times experience approximately five putative interaction partners in its immediate cellular environment. Associated thermodynamic parameters are in Table 1 and Table S2. Jens Danielsson et al. PNAS 2015;112:40:12402-12407 ©2015 by National Academy of Sciences