The fact that cleavage of single peptide linkages in proteins often leads to extensive conformational alteration, including regions far removed from the cleavage site is not fully understood. We propose, based on the work of Linderstrom-Lang and Schellman, that disruption primarily occurs within protein structural domains that are stabilized by cooperative interactions and that cleavage of single peptide linkages of the domain perturbs the entire cooperative interaction. For this model we review experimental observations: on fragment complexation (ribonuclease A, staphylococcal nuclease and cytochrome c), destabilized N-terminal large fragments (ribonuclease A and nuclease), cooperative folding and stabilization of proteins (ribonuclease A, nuclease and cytochrome c), the close relationship of the three-dimensional structure between fragment complexes and the original protein (ribonuclease A and nuclease), ligand induced stabilization (nuclease), 3D domain swapping, circular permutation (dihydrofolate reductase), evolutionary conservation (cytochrome c fold). Based on analysis of these observations, we conclude that the cooperative interactions of domains are important for the mechanism of 3D domain swapping as well as for stabilization and thereby, determination of the ground state of native proteins. Furthermore, analysis of the observations reveals that domains generally contain a hydrophobic core. Further, based on studies of cytochrome c and the Tsao, Evans and Wennerstrom model of electrostatic interactions between two hydrophobic monolayers, we propose the model that the hydrophobic core of a domain is polarizable and responds to the surface charges through its polarizability to stabilize the domain, explaining in part the nature of the cooperative interactions.