Towards an understanding of RNA structural modalities: a riboswitch case study.

Hee Rhang Yoon,Christine Heitsch,Alain Laederach,Aaztli Coria

doi:10.1515/cmb-2019-0004

Abstract

A riboswitch is a type of RNA molecule that regulates important biological functions by changing structure, typically under ligand-binding. We assess the extent that these ligand-bound structural alternatives are present in the Boltzmann sample, a standard RNA secondary structure prediction method, for three riboswitch test cases. We use the cluster analysis tool RNAStructProfiling to characterize the different modalities present among the suboptimal structures sampled. We compare these modalities to the putative base pairing models obtained from independent experiments using NMR or fluorescence spectroscopy. We find, somewhat unexpectedly, that profiling the Boltzmann sample captures evidence of ligand-bound conformations for two of three riboswitches studied. Moreover, this agreement between predicted modalities and experimental models is consistent with the classification of riboswitches into thermodynamic versus kinetic regulatory mechanisms. Our results support cluster analysis of Boltzmann samples by RNAStructProfiling as a possible basis for de novo identification of thermodynamic riboswitches, while highlighting the challenges for kinetic ones.

Highlights

Unlike Deoxy riboNucleic Acid (DNA), RiboNucleic Acid (RNA) exists in the cell as a single-stranded polymer molecule [14, 44]
We assess the extent that these ligand-bound structural alternatives are present in the Boltzmann sample, a standard RNA secondary structure prediction method, for three riboswitch test cases
Most algorithms used to predict RNA secondary structure are based on the nearest neighbor thermodynamic model (NNTM) [25, 41]

Summary

Introduction

Unlike Deoxy riboNucleic Acid (DNA), RiboNucleic Acid (RNA) exists in the cell as a single-stranded polymer molecule [14, 44]. Predictions of suboptimal structures [48, 49] and of base pairing probabilities under the Boltzmann partition function [12, 23, 26] have long been used to complement MFE predictions. These two approaches are uni ed by the method of sampling suboptimal secondary structures from the Boltzmann ensemble [5]. These Boltzmann sample predictions often reveal that the suboptimal secondary structures are organized into two or more distinct modalities [4, 20, 31, 42]

Methods

Results

Conclusion