Protein structures, folds and fold spaces

There has been considerable progress towards the goal of understanding the space of possible tertiary structures adopted by proteins. Despite a greatly increased rate of structure determination and a deliberate strategy of sequencing proteins expected to be very different from those already known, it is now rare to see a genuinely new fold, leading to the conclusion that we have seen the majority of natural structural types. The increase in knowledge has also led to a critical examination of traditional fold-based classifications and their meaning for evolution and protein structures. We review these issues and discuss possible solutions.