Sequence-dependent conformational preferences of disordered single-stranded RNA

Disordered single-stranded RNA (ssRNA) molecules, like their well-folded counterparts, have crucial functions that depend on their structures. However, since native ssRNAs constitute a highly heterogeneous conformer population, their structural characterization poses challenges. One important question regards the role of sequence in influencing ssRNA structure. Here, we adopt an integrated approach that combines solution-based measurements, including small-angle X-ray scattering (SAXS) and Förster resonance energy transfer (FRET), with experimentally guided all-atom molecular dynamics (MD) simulations, to construct structural ensembles of a 30-nucleotide RNA homopolymer (rU30) and a 30-nucleotide RNA heteropolymer with an A-/C-rich sequence. We compare the size, shape, and flexibility of the two different ssRNAs. While the average properties align with polymer-physics descriptions of flexible polymers, we discern distinct, sequence-dependent conformations at the molecular level that demand a more detailed representation than provided by polymer models. These findings emphasize the role of sequence in shaping the overall properties of ssRNA.