TY - JOUR T1 - Cross-Over between Discrete and Continuous Protein Structure Space: Insights into Automatic Classification and Networks of Protein Structures A1 - Pascual-García, Alberto A1 - Abia, David A1 - Ortiz, Ángel R. A1 - Bastolla, Ugo Y1 - 2009/03/27 N2 - Author Summary Making order of the fast-growing information on proteins is essential for gaining evolutionary and functional knowledge. The most successful approaches to this task are based on classifications of protein structures, such as SCOP and CATH, which assume a discrete view of the protein structure space as a collection of separated equivalence classes (folds). However, several authors proposed that protein domains should be regarded as assemblies of polypeptide fragments, which implies that the protein–structure space is continuous. Here, we assess these views of domain space through the concept of transitivity; i.e., we test whether structure similarity of A with B and B with C implies that A and C are similar, as required for consistent classification. We find that the domain space is approximately transitive and discrete at high similarity and continuous at low similarity, where transitivity is severely violated. Comparing our classification at the cross-over similarity with CATH and SCOP, we find that they join proteins at low similarity where classification is inconsistent. Part of this discrepancy is due to structural divergence of homologous domains, which are forced to be in a single cluster in CATH and SCOP. Structural and evolutionary relationships between consistent clusters are represented as a network in our approach, going beyond current protein classification schemes. We conjecture that our results are related to a change of evolutionary regime, from uniparental divergent evolution for highly related domains to assembly of large fragments for which the classical tree representation is unsuitable. JF - PLOS Computational Biology JA - PLOS Computational Biology VL - 5 IS - 3 UR - https://doi.org/10.1371/journal.pcbi.1000331 SP - e1000331 EP - PB - Public Library of Science M3 - doi:10.1371/journal.pcbi.1000331 ER -