Format

Send to

Choose Destination
Proc Natl Acad Sci U S A. 2019 Aug 20;116(34):16847-16855. doi: 10.1073/pnas.1901530116. Epub 2019 Aug 2.

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

Author information

1
Department of Biochemistry, Stanford University, Stanford, CA 94305.
2
Program in Biophysics, Stanford University, Stanford, CA 94305.
3
Department of Biochemistry, Stanford University, Stanford, CA 94305; herschla@stanford.edu wjg@stanford.edu rhiju@stanford.edu.
4
Department of Chemistry, Stanford University, Stanford, CA 94305.
5
Stanford ChEM-H (Chemistry, Engineering, and Medicine for Human Health), Stanford University, Stanford, CA 94305.
6
Program in Biophysics, Stanford University, Stanford, CA 94305; herschla@stanford.edu wjg@stanford.edu rhiju@stanford.edu.
7
Department of Genetics, Stanford University, Stanford, CA 94305.
8
Department of Applied Physics, Stanford University, Stanford, CA 94305.
9
Chan Zuckerberg Biohub, San Francisco, CA 94158.
10
Department of Physics, Stanford University, Stanford, CA 94305.

Abstract

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-∆∆G. 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.

KEYWORDS:

RNA energetics; blind prediction; high-throughput data; indirect readout

PMID:
31375637
PMCID:
PMC6708322
DOI:
10.1073/pnas.1901530116
[Indexed for MEDLINE]
Free PMC Article

Supplemental Content

Full text links

Icon for HighWire Icon for PubMed Central
Loading ...
Support Center