On Protein Loops, Prior Molecular States and Common Ancestors of Life

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

Research output: Contribution to journalReview articlepeer-review


The principle of continuity demands the existence of prior molecular states and common ancestors responsible for extant macromolecular structure. Here, we focus on the emergence and evolution of loop prototypes – the elemental architects of protein domain structure. Phylogenomic reconstruction spanning superkingdoms and viruses generated an evolutionary chronology of prototypes with six distinct evolutionary phases defining a most parsimonious evolutionary progression of cellular life. Each phase was marked by strategic prototype accumulation shaping the structures and functions of common ancestors. The last universal common ancestor (LUCA) of cells and viruses and the last universal cellular ancestor (LUCellA) defined stem lines that were structurally and functionally complex. The evolutionary saga highlighted transformative forces. LUCA lacked biosynthetic ribosomal machinery, while the pivotal LUCellA lacked essential DNA biosynthesis and modern transcription. Early proteins therefore relied on RNA for genetic information storage but appeared initially decoupled from it, hinting at transformative shifts of genetic processing. Urancestral loop types suggest advanced folding designs were present at an early evolutionary stage. An exploration of loop geometric properties revealed gradual replacement of prototypes with α-helix and β-strand bracing structures over time, paving the way for the dominance of other loop types. AlphFold2-generated atomic models of prototype accretion described patterns of fold emergence. Our findings favor a ‛processual’ model of evolving stem lines aligned with Woese’s vision of a communal world. This model prompts discussing the ‘problem of ancestors’ and the challenges that lie ahead for research in taxonomy, evolution and complexity.

Original languageEnglish (US)
JournalJournal of Molecular Evolution
StateAccepted/In press - 2024


  • Folds
  • Molecular evolution
  • Origin of life
  • Phylogenomic analysis
  • Structural domains
  • Tree of life

ASJC Scopus subject areas

  • Genetics
  • Ecology, Evolution, Behavior and Systematics
  • Molecular Biology


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