Tracing the birth of structural domains from loops during protein evolution

M. Fayez Aziz, Fizza Mughal, Gustavo Caetano-Anollés

Research output: Contribution to journalArticlepeer-review


The structures and functions of proteins are embedded into the loop scaffolds of structural domains. Their origin and evolution remain mysterious. Here, we use a novel graph-theoretical approach to describe how modular and non-modular loop prototypes combine to form folded structures in protein domain evolution. Phylogenomic data-driven chronologies reoriented a bipartite network of loops and domains (and its projections) into ‘waterfalls’ depicting an evolving ‘elementary functionome’ (EF). Two primordial waves of functional innovation involving founder ‘p-loop’ and ‘winged-helix’ domains were accompanied by an ongoing emergence and reuse of structural and functional novelty. Metabolic pathways expanded before translation functionalities. A dual hourglass recruitment pattern transferred scale-free properties from loop to domain components of the EF network in generative cycles of hierarchical modularity. Modeling the evolutionary emergence of the oldest P-loop and winged-helix domains with AlphFold2 uncovered rapid convergence towards folded structure, suggesting that a folding vocabulary exists in loops for protein fold repurposing and design.

Original languageEnglish (US)
Article number14688
JournalScientific reports
Issue number1
StatePublished - Dec 2023

ASJC Scopus subject areas

  • General


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