Characterization of cross-family conserved fragments

Abstract

In a companion study, we introduced ProDive and used it to identify 318,289 high-confidence cross-family segment correspondences across all 25,545 Pfam families. Here we characterize the pervasiveness and biophysical context of the resulting mapped fragment resource. Graph-based community analysis shows that segment reuse is broadly distributed across the protein family universe, with thousands of mostly small modules rather than concentration in a small number of family pairs. Comparison between Pfam families and de novo designed proteins reveals an approximately 2.1-fold enrichment of cross-family segment correspondences relative to the Pfam-Pfam background. Mapped fragments are strongly enriched in helix-dominant secondary structures with intermediate solvent exposure, occupy a narrowed sequence-context entropy regime, and show a significant shift toward lower fragment-associated contact order relative to random control windows, directly supporting a folding-compatible local structural regime. Matched annotation analyses show depletion from known domain-based interaction interfaces and mild depletion from strict DisProt disorder. Direct Start2Fold/HDX and{varphi} -value comparisons are limited in scale but connect the same fragment class to folding-related protection: stability annotations support local structural stabilization that may facilitate folding, whereas folding annotations and transition-state enrichments provide more specific evidence for folding initiation or pathway involvement. Together, these results support a physical-constraint interpretation of local structural conservation, in which reusable compact fragments contribute prominently to local stability and folding-relevant local structure, with folding initiation supported in specific subsets rather than as an exclusive mechanism.