Development of a motif-based topology-independent structure comparison method to identify evolutionarily related folds

Joseph M. Dybas, Andras Fiser

Research output: Contribution to journalArticlepeer-review

6 Scopus citations


Structure conservation, functional similarities, and homologous relationships that exist across diverse protein topologies suggest that some regions of the protein fold universe are continuous. However, the current structure classification systems are based on hierarchical organizations, which cannot accommodate structural relationships that span fold definitions. Here, we describe a novel, super-secondary-structure motif-based, topology-independent structure comparison method (SmotifCOMP) that is able to quantitatively identify structural relationships between disparate topologies. The basis of SmotifCOMP is a systematically defined super-secondary-structure motif library whose representative geometries are shown to be saturated in the Protein Data Bank and exhibit a unique distribution within the known folds. SmotifCOMP offers a robust and quantitative technique to compare domains that adopt different topologies since the method does not rely on a global superposition. SmotifCOMP is used to perform an exhaustive comparison of the known folds and the identified relationships are used to produce a nonhierarchical representation of the fold space that reflects the notion of a continuous and connected fold universe. The current work offers insight into previously hypothesized evolutionary relationships between disparate folds and provides a resource for exploring novel ones. Proteins 2016; 84:1859–1874.

Original languageEnglish (US)
Pages (from-to)1859-1874
Number of pages16
JournalProteins: Structure, Function and Bioinformatics
Issue number12
StatePublished - Dec 1 2016


  • Smotif
  • fold evolution
  • structure classification
  • structure comparison
  • super-secondary structure motif

ASJC Scopus subject areas

  • Structural Biology
  • Biochemistry
  • Molecular Biology


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