Thermodynamic Control of Ribosomal Frameshifting

Ribosomal translation of mRNA proceeds by decoding three nucleotides at a time and spontaneous changes of the reading frame are rare. However, specific mRNA sequences can guide the ribosome to shift the reading frame. Programmed ？1 ribosomal frameshifting occurs while two tRNAs are bound to a slippery-sequence motif of the mRNA. Mutations of the slippery sequence have dramatic effects on the frameshift efficiency. In this study, employing Bayesian statistics, we build a model to obtain the free energies of the base pairs in the 0 and ？1 frames. Our results show that the frameshift effciencies can be reproduced and even predicted from the free energies of the tRNA-mRNA base pairs present in both frames. The observation that the free-energy difference determines the probability of ending up in either reading frame indicates that the ribosome is paused to such a degree that the free-energy barrier hindering the change of the reading frame can be overcome. Therefore, frameshifting is controlled by thermodynamics and not by kinetics. Further, the base-pair free energies obtained from our analysis allow us to quantify the effect that the ribosomal environment has on the strength of the base pairs