Chemical Biology of Double Helical and Non-Double Helical Nucleic Acids: “To B or Not To B, That Is the Question”

Abstract

Abstract Nucleic acids form not only the canonical double helix (duplex) but also the non-canonical (non-double helix) structures such as triplexes, G-quadruplexes, and i-motifs. The formation of these non-canonical structures and their stabilities depend on the microscopic environmental conditions around the nucleic acids. The intracellular environments, where various molecules are densely packed, exhibit molecular crowding. The non-canonical structures are very stable under molecular crowding conditions. The functions and structures of these nucleic acids in cells are optimized to enable them to function well in the crowded environments. We envisaged that molecular crowding in cells may play an important role in the reactions involving functionalized biomolecules and discovered a novel regulatory mechanism underlying the role of the non-canonical structures in gene expression. Based on the results of our work, we have developed novel methods to control the gene expression of non-double helical nucleic acids, leading to new insights into the chemistry of such nucleic acids. Our major achievements are summarized in this review.