The Four mRNA Bases Have Quite Different (Un)folding Free Energies, Applications to RNA Splicing and Translation Initiation with BindOligoNet

J Mol Biol. 2022 Jun 15;434(11):167578. doi: 10.1016/j.jmb.2022.167578. Epub 2022 Apr 6.

Abstract

Expression of mRNA is often regulated by the binding of a small RNA (miRNA, snoRNA, siRNA). While the pairing contribution to the net free energy is well parameterized and can be computed in O(N) time, the cost of removing pre-existing mRNA secondary structure has not received sufficient attention. Conventional methods for computing the unfolding free energy of a target mRNA are costly, scaling like the cube of the number of target bases O(N3). Here we introduce a model to describe the unfolding costs of the binding site, which features surprisingly big differences in the free energy parameters for the four bases. The model is implemented in our O(N) algorithm, BindOligoNet. Donor splice site prediction is more accurate when using our calculation of spliceosomal U1-snRNA to mRNA net binding free energy. Our base-dependent free energies also correlate with efficient ribosome docking near the start codon.

Keywords: Small RNA; gene regulation; messenger RNA; nucleic acids; ribosome initiation.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Algorithms
  • Binding Sites
  • Nucleic Acid Conformation
  • Nucleotides
  • Peptide Chain Initiation, Translational*
  • RNA Splicing*
  • RNA, Messenger* / biosynthesis
  • RNA, Messenger* / chemistry
  • RNA, Small Nuclear / chemistry
  • Spliceosomes / chemistry
  • Thermodynamics

Substances

  • Nucleotides
  • RNA, Messenger
  • RNA, Small Nuclear
  • U1 small nuclear RNA