ProDive reveals pervasive cross-family protein fragment reuse

Chen, X.; Tian, P.

doi:10.64898/2026.04.02.715841

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bioRxiv · 10.64898/2026.04.02.715841

ProDive reveals pervasive cross-family protein fragment reuse

Chen, X.·Tian, P.

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Abstract

Cross-family reuse of short protein fragments has been a long-standing mystery whose resolution first demands an algorithm for their systematic detection. Here we introduce ProDive, a closed-form symmetric KL divergence between profile HMMs that enables GPU-accelerated, fragment-level screening across all 25,545 Pfam families. ProDive identifies [~]318,000 cross-family fragment correspondences involving compact cores of 8-13 residues with RMSD values far below random background. Their organisation into diverse graph communities and four-fold enrichment in de novo designed proteins point away from family-specific functions and toward a general biophysical property. Their helix dominance and moderate solvent exposure suggest a role in folding initiation--a link corroborated by overlap with experimentally measured{phi} -values and by a monotonic density gradient across disordered regions. Together, these observations converge on a single explanation: cross-family fragment reuse likely reflects shared requirements for early structure formation during folding, the one biophysical constraint common to all proteins.

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Chen, X., Tian, P.. 2026-04-05. ProDive reveals pervasive cross-family protein fragment reuse. https://doi.org/10.64898/2026.04.02.715841

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