The folding of a domain is essentially based on a complex network of sequential inter-molecular interactions in time [49] . This has of course significant implications for domain integrity, particularly if one assumes that the core of a protein domain is and has to be largely structurally conserved. Indeed, even single mutations that arise in this area may easily derail the folding process, either because their free energy contribution influences residues in the direct vicinity or disturbs connections higher up in the intermolecular network [49] . It is therefore hypothesized that protein evolution took place at the periphery of the protein domain core, and that gradual changes via point mutations, insertions and deletions in surface loops brought about the evolutionary distance we see among proteins to date [21, [50] [51] [52] .