RNA molecules maintain conserved three-dimensional (3D) structures despite extensive sequence variability, underpinning diverse biological functions. The mechanisms enabling such structural conservation amid sequence diversity remain incompletely understood. In this chapter, we analyze RNA tertiary interactions across homologous sequences using structural alignments and reveal pervasive 3D molecular neutrality or a tolerance of local sequence variations through isosteric and conformational accommodations. These RNA molecular properties allow many sequences to fold into similar architectures with minimal conserved nucleotides. Further, molecular neutrality facilitates evolutionary innovations via alternative conformations, epistasis, and allosteric effects. Our findings highlight how structure-based molecular neutrality shapes RNA evolvability, providing a framework to interpret RNA structural diversity and the emergence of novel functions. It is hoped that the deep links between structural sequence alignments and RNA folding principles will help the design of RNA prediction tools.

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Structural Neutrality and Accommodation Shape RNA Evolution

  • Eric Westhof

摘要

RNA molecules maintain conserved three-dimensional (3D) structures despite extensive sequence variability, underpinning diverse biological functions. The mechanisms enabling such structural conservation amid sequence diversity remain incompletely understood. In this chapter, we analyze RNA tertiary interactions across homologous sequences using structural alignments and reveal pervasive 3D molecular neutrality or a tolerance of local sequence variations through isosteric and conformational accommodations. These RNA molecular properties allow many sequences to fold into similar architectures with minimal conserved nucleotides. Further, molecular neutrality facilitates evolutionary innovations via alternative conformations, epistasis, and allosteric effects. Our findings highlight how structure-based molecular neutrality shapes RNA evolvability, providing a framework to interpret RNA structural diversity and the emergence of novel functions. It is hoped that the deep links between structural sequence alignments and RNA folding principles will help the design of RNA prediction tools.