Sequence-dependent RNA helix conformational preferences predictably impact tertiary structure formation

• Published in: Proceedings of the National Academy of Sciences - PNAS Vol. 116; no. 34; pp. 16847 - 16855
• Main Authors: Yesselman, Joseph D., Denny, Sarah K., Bisaria, Namita, Herschlag, Daniel, Greenleaf, William J., Das, Rhiju
• Format: Journal Article
• Language: English
• Published: United States National Academy of Sciences 20.08.2019
• Series: PNAS Plus
• Subjects: Base Pairing; Base pairs; Base Sequence; Biological activity; Biological Sciences; Computer applications; Gene expression; Model accuracy; Models, Molecular; Nucleic Acid Conformation; Nucleotide sequence; Nucleotides; PNAS Plus; Protein structure; Proteins; Ribonucleic acid; RNA; RNA - chemistry; RNA - genetics; RNA Stability; Structural stability; Tertiary structure; Thermodynamics; Variations; indirect readout; high-throughput data; RNA energetics; blind prediction
• ISSN: 0027-8424; 1091-6490
• DOI: 10.1073/pnas.1901530116

Structured RNAs and RNA complexes underlie biological processes ranging from control of gene expression to protein translation. Approximately 50% of nucleotides within known structured RNAs are folded into Watson–Crick (WC) base pairs, and sequence changes that preserve these pairs are typically assumed to preserve higher-order RNA structure and binding of macromolecule partners. Here, we report that indirect effects of the helix sequence on RNA tertiary stability are, in fact, significant but are nevertheless predictable from a simple computational model called RNAMake-ΔΔG. When tested through the RNA on a massively parallel array (RNA-MaP) experimental platform, blind predictions for >1500 variants of the tectoRNA heterodimer model system achieve high accuracy (rmsd 0.34 and 0.77 kcal/mol for sequence and length changes, respectively). Detailed comparison of predictions to experiments support a microscopic picture of how helix sequence changes subtly modulate conformational fluctuations at each base-pair step, which accumulate to impact RNA tertiary structure stability. Our study reveals a previously overlooked phenomenon in RNA structure formation and provides a framework of computation and experiment for understanding helix conformational preferences and their impact across biological RNA and RNA-protein assemblies.