RNA Structure: Past, Future, and Gene Therapy Applications

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 RNA or other biopolymers or quaternary structure, or with metabolites and biomolecules or quinary structure, RNA structure plays a critical role in RNA’s lifecycle from transcription to decay and many cellular processes. In contrast to success with 3-dimensional protein structure prediction using AlphaFold, RNA tertiary and beyond structures prediction remains challenging. However, approaches involving machine learning and artificial intelligence, sequencing of RNA and its modifications, and structural analyses at the single-cell and intact tissue levels, among others, provide an optimistic outlook for the continued development and refinement of RNA-based applications. Here, we highlight those in gene therapy.