RNA structure

RNA structure begins with a single-stranded polymer whose ribose-phosphate backbone carries the bases adenine, uracil, guanine, and cytosine. The ribose 2′-hydroxyl group distinguishes RNA from DNA and promotes conformational flexibility, but also makes RNA more susceptible to alkaline hydrolysis. Primary structure is the nucleotide sequence; secondary structure describes recurring base-paired elements, usually represented with stems, loops, bulges, and junctions. Watson–Crick pairs provide much of the framework, while noncanonical pairs expand the possible geometries. Tertiary structure is the complete three-dimensional arrangement, including contacts between distant parts of a chain. These levels are connected rather than strictly separate: a sequence encodes tendencies to fold, while tertiary contacts can stabilize secondary structures that would otherwise be weak.¹

RNA folding is governed by competing interactions that produce ensembles of related conformations rather than one permanently fixed shape. Stem-loops are common building blocks, while internal loops and multibranch junctions provide the flexibility needed to redirect a chain. A pseudoknot forms when bases in a loop pair with a later region, crossing the nesting pattern of ordinary secondary structure; pseudoknots occur in ribozymes, viral genomes, and programmed ribosomal frameshifting signals.² A-minor interactions, base triples, coaxial stacking, and metal-ion-mediated contacts are important tertiary motifs. Magnesium ions often stabilize compact folds by screening phosphate repulsion, although proteins and small molecules may supply additional contacts or reshape the fold. The resulting structures can act as molecular switches in riboswitches and catalytic centers in ribozymes.³

RNA structures are studied by combining experimental measurements with computational models. X-ray crystallography and cryo-electron microscopy can reveal atomic or near-atomic arrangements in sufficiently ordered RNA molecules and RNA–protein assemblies; nuclear magnetic resonance spectroscopy is especially useful for smaller, mobile systems. Chemical probing methods modify accessible or reactive nucleotides, allowing techniques such as SHAPE and dimethyl sulfate mapping to infer base pairing and flexibility across transcripts.⁴ Prediction programs generally estimate energetically favorable secondary structures, but pseudoknots, tertiary contacts, ligand effects, molecular crowding, and alternative conformations remain difficult. Structural databases such as the Protein Data Bank preserve experimentally determined RNA-containing coordinates, while Rfam and RNAcentral organize sequence families and annotations that help connect conserved sequence patterns with structural motifs.⁵⁶

RNA structure includes chemically modified and transient states that are often invisible in simplified diagrams. More than one hundred naturally occurring RNA modifications can alter base-pairing, stacking, local flexibility, or recognition by proteins and small molecules; modifications are particularly consequential in transfer RNA and ribosomal RNA.⁷ Some RNAs fold cotranscriptionally, so the order in which segments emerge from RNA polymerase can determine which competing structure forms. Others remain intrinsically disordered until they bind a partner, as in many ribonucleoprotein complexes. Viral RNA genomes exploit compact pseudoknots, internal initiation elements, and long-range contacts to control translation and replication. RNA structure is therefore not merely a static scaffold: it can encode regulation in shape, alter accessibility to nucleases and enzymes, and provide a route by which sequence variation changes molecular function without changing a protein-coding region.

Primary structure

The linear nucleotide sequence of an RNA molecule.

Secondary structure

The pattern of local and long-range base pairing, commonly depicted as stems and loops.

Tertiary structure

The complete three-dimensional fold produced by interactions among secondary-structure elements.

Pseudoknot

A folded arrangement in which bases in a loop pair with a downstream sequence, creating crossing interactions.

Ribozyme

An RNA molecule with catalytic activity.

Riboswitch

A structured RNA regulatory element that changes conformation after binding a small molecule.