RNA Structure: Historical and Future Perspectives

First believed to be a simple intermediary between the information encoded in deoxyribonucleic acid and that functionally displayed in proteins, ribonucleic acid (RNA) is now known to have many functions through its abundance and intricate, ubiquitous, diverse, and dynamic structure. About 70-90% of the human genome is transcribed into protein-coding and noncoding RNAs as main determinants along with regulatory sequences of cellular to populational biological diversity. From the nucleotide sequence or primary structure, through Watson-Crick pairing self-folding or secondary structure, to compaction via longer distance Watson-Crick and non-Watson-Crick interactions or tertiary structure, and interactions with other biopolymers or quaternary structure, or with metabolites or quinary structure, RNA structure plays a critical role in RNA’s lifecycle from transcription to decay. In contrast to the success with 3-dimensional protein structure prediction using AlphaFold, determining and predicting RNA tertiary and beyond structures remains challenging. However, many approaches have been introduced or are being worked on relying on the use of machine learning and artificial intelligence, sequencing of RNA and its modifications, and structural analyses at the single cell and intact tissue levels, among others. These approaches provide an optimistic outlook for the continued development and refinement of RNA-based applications in medicine, agriculture, and industry.