RESEARCH ARTICLE Structural Bridges through Fold Space

Several protein structure classification schemes exist that partition the protein universe into structural units called folds. Yet these schemes do not discuss how these units sit relative to each other in a global structure space. In this paper we construct networks that describe such global relationships between folds in the form of structural bridges. We generate these networks using four different structural alignment methods across multiple score thresholds. The networks constructed using the different methods remain a similar distance apart regardless of the probability threshold defining a structural bridge. This suggests that at least some structural bridges are method specific and that any attempt to build a picture of struc-tural space should not be reliant on a single structural superposition method. Despite these differences all representations agree on an organisation of fold space into five principal com-munity structures: all-α, all-β sandwiches, all-β barrels, α/β and α + β. We project estimated fold ages onto the networks and find that not only are the pairings of unconnected folds asso-ciated with higher age differences than bridged folds, but this difference increases with the number of networks displaying an edge. We also examine different centrality measures fo