CHAPTER 2: DNA and RNA Structure^†

This chapter explores the foundational principles of the conformations of nucleosides, nucleotides and oligonucleotides and the structures of the various double-helical, three-stranded and four-stranded DNA molecules as well as the expanding universe of RNA tertiary structural motifs. At the lower end of the molecular scale, the pursuit of novel nucleoside and nucleotide analogues with antiviral activity and as building blocks for oligonucleotides against a multitude of therapeutic targets requires the steady generation of new structural information to guide synthetic efforts to improve drug potency and efficacy. X-ray crystallography, solution nuclear magnetic resonance, cryo-electron microscopy, spectroscopy, computational simulation and combinations of these approaches are penetrating ever more complex molecular assemblies and machines to reveal their inner workings and underlying chemical principles. Stunning improvements in optical microscopy, as well as electron microscopic tomography, neutron and electron diffraction, have set the stage for exciting structural breakthroughs and discoveries we can anticipate during the coming years. At times, structure and function seem out of step and we rely on the former to deliver a better understanding of the latter. A fine example is left-handed Z-DNA that we have described here in some detail. Over 40 years after the initial determination of the crystal structure of a Z-DNA duplex, increasing evidence has been uncovered that supports important roles of CG-repeat sequences and left-handed DNA in cell development, regulation and disease.