 It has been found that the folding of an isolated domain can take place at the same rate or sometimes faster than that of the integrated domain, suggesting that unfavourable interactions with the rest of the protein can occur during folding.Several arguments suggest that the slowest step in the folding of large proteins is the pairing of the folded domains.This is either because the domains are not folded entirely correctly or because the small adjustments required for their interaction are energetically unfavourable, such as the removal of water from the domain interface.