Insights from Crystallographic Studies into the Structural and Pairing Properties of Nucleic Acid Analogs and Chemically Modified DNA and RNA Oligonucleotides

Abstract

Chemically modified nucleic acids function as model systems for native DNA and RNA; as chemical probes in diagnostics or the analysis of protein–nucleic acid interactions and in high-throughput genomics and drug target validation; as potential antigene-, antisense-, or RNAi-based drugs; and as tools for structure determination (i.e., crystallographic phasing), just to name a few. Biophysical and structural investigations of chemically modified DNAs and RNAs, particularly of nucleic acid analogs with more significant alterations to the well-known base-sugar-phosphate framework (i.e., peptide or hexopyranose nucleic acids), can also provide insights into the properties of the natural nucleic acids that are beyond the reach of studies focusing on DNA or RNA alone. In this review we summarize results from crystallographic analyses of chemically modified DNAs and RNAs that are primarily of interest in the context of the discovery and development of oligonucleotide-based therapeutics. In addition, we re-examine recent structural data on nucleic acid analogs that are investigated as part of a systematic effort to rationalize nature's choice of pentose in the genetic system.