(A) The ground state (center) is in equilibrium with two native (or working) conformations. Exchange process I leads to the formation of a dimer, with the changes being localized to the surface that forms the interface between the two SOD1 monomers in Cu2Zn2SOD1S-S (left); exchange process II folds the electrostatic loop within the enzyme to form a helix (pink). (B) The ground state (center) is also in equilibrium with two non-native conformations, both of which have aberrant dimer interfaces. These interfaces and the unstructured electrostatic loop in apoSOD12SH may act as sites for the formation of higher-order oligomers and aggregates that may have a role in ALS. The binding sites for metal ions are denoted by purple circles (Zn) and khaki circles (Cu); these sites are empty (denoted by E) for all these states. P is the percentage of enzymes in a state; τ is the lifetime of the state.