DaliScope: Distilling Biological Insights from Deep Structural Alignments

Abstract

Structural similarity searches reveal protein relationships that sequence alignments miss, but treating DALI results as isolated match lists misses deeper connections. We present DaliScope, an interactive Python framework that treats complete DALI target sets as structured populations for systematic analysis of protein structural neighbourhoods. DaliScope combines structural community detection with sequence profiling, Pfam annotation, residue mapping, and 3D visualization, enabling target sets to be subdivided and examined at the residue level. We demonstrate two applications. In a multidomain protein with sparse domain annotation, structural analysis uncovered previously unannotated domains. A structurally anchored HxD...H signature occurred in 697 of 1,093 Pfam-annotated CUPIN domains and in 15 domains lacking Pfam annotation; relaxing the central residue constraint recovered 96% of Pfam-annotated CUPIN domains among the DALI targets. In a second application, a DALI search with transitive closure returned >12,000 hits. Applying an 80% coverage criterion to a conserved structural core reduced this set to 6,708 domain instances, resolved into 23 structural communities. (80% was chosen instead of the default 50% because the GOLD domain has a compact core with short loops.) Many communities were strongly enriched for individual Pfam families while providing structural context for 1,097 targets lacking Pfam assignments. Three-dimensional superimposition revealed structural continuity among related {beta}-sandwich architectures through progressive changes in sheet geometry and auxiliary elements. Together, these examples show how a single DALI query provides a structural anchor for organizing large neighbourhoods, extending interpretation beyond sequence-based annotations, and deriving structurally anchored sequence signatures from defined populations.