Single-Crystal X-Ray Diffraction Studies of Oligonucleotides and Oligonucleotide-Drug Complexes

Nucleic acids constitute the library of genetic information for all living organisms. They also play a regulatory role in many biological events concerned with the utilization of genetic information. The double‐helical model of DNA, proposed by Watson and Crick in 1953, suggested the structural basis for its biological role, but this insight into nucleic acid structures seems to have generated as many questions as it has provided answers. Experimental studies, in particular fiber diffraction work, yielded a wealth of information on the conformational flexibility of nucleic acids and on the importance of interactions with water and cations. Major advances in synthetic organic chemistry, with implications for molecular biology, propelled nucleic acid research forward in the late 1970s. The availability of milligram quantities of synthetic oligonucleotides of defined sequence and high purity paved the way for detailed and accurate structural analysis using single‐crystal X‐ray diffraction methods and, in more recent times, NMR spectroscopy. This article is a detailed survey of the structural results generated by crystallographic techniques as applied to DNA, RNA, and nucleic acid–drug complexes over the period 1979–1990. The appendix lists important definitions used in the characterization of oligonucleotide structures. The extreme flexibility of the DNA conformation is only one result of X‐ray structure studies on single crystals of oligonucleotides, which are reviewed here. Thus both the small and the large grooves of A‐type helices can be very different in size; in one oligonucleotide A‐ and B‐type helices coexist (see picture at the right, where the B‐type helices fill a tunnel formed by one of the A‐type helices); mismatched base pairs often disturb the overall conformation amazingly little. Of extreme importance (also for the synthesis of medicaments) are insights into the way the active molecules interact with the oligonucleotides.