The inner β-barrel is in many cases stabilized by intricate salt-bridge networks. Loops at the C-terminal ends of the β-barrel are responsible for catalytic activity while N-terminal loops are important for the stability of the TIM-barrels. Structural inserts ranging from extended loops to independent domains may be inserted in place of these loops or at the N/C-terminals. TIM barrels appear to have evolved through gene duplication and domain fusion events of half-barrel proteins, with a majority of TIM barrels originating from a common ancestor. This lead many TIM barrels to possess internal symmetries. Further gene duplication events of this ancestral TIM barrel lead to diverging enzymes possessing the functional diversity observed today. TIM barrels have also been a longstanding target for protein designers. Successful TIM barrel designs include both domain fusions of existing proteins and "de novo" designs. Domain fusions experiments have resulted in many successful designs, whereas "de novo" designs only yielded successes after 28 years of incremental development.