RNA molecules with conserved catalytic cores but variable peripheries fold along unique energetically optimized pathways

Somdeb Mitra, Alain Laederach, Barbara L. Golden, Russ B. Altman, Michael Brenowitz

Research output: Contribution to journalArticlepeer-review

19 Scopus citations


Functional and kinetic constraints must be efficiently balanced during the folding process of all biopolymers. To understand how homologous RNA molecules with different global architectures fold into a common core structure we determined, under identical conditions, the folding mechanisms of three phylogenetically divergent group I intron ribozymes. These ribozymes share a conserved functional core defined by topologically equivalent tertiary motifs but differ in their primary sequence, size, and structural complexity. Time-resolved hydroxyl radical probing of the backbone solvent accessible surface and catalytic activity measurements integrated with structural-kinetic modeling reveal that each ribozyme adopts a unique strategy to attain the conserved functional fold. The folding rates are not dictated by the size or the overall structural complexity, but rather by the strength of the constituent tertiary motifs which, in turn, govern the structure, stability, and lifetime of the folding intermediates. A fundamental general principle of RNA folding emerges from this study: The dominant folding flux always proceeds through an optimally structured kinetic intermediate that has sufficient stability to act as a nucleating scaffold while retaining enough conformational freedom to avoid kinetic trapping. Our results also suggest a potential role of naturally selected peripheral A-minor interactions in balancing RNA structural stability with folding efficiency.

Original languageEnglish (US)
Pages (from-to)1589-1603
Number of pages15
Issue number8
StatePublished - Aug 2011


  • Group I introns
  • Kinetic intermediates
  • RNA folding
  • Ribozymes
  • Structural homology

ASJC Scopus subject areas

  • Molecular Biology


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