1. Introduction 2551.1 General thermodynamics 2562. Nucleic acid thermodynamics 2602.1 DNA duplexes 2612.2 RNA duplexes 2632.3 Hybrid DNA–RNA duplexes 2642.4 Hydration 2672.5 Conformational flexibility 2692.6 Thermodynamics 2723. Nucleic acid–ligand interactions 2773.1 Minor groove binders 2783.2 DNA intercalators 2843.3 Triple-helical systems 2883.3.1 Structures 2883.3.2 Hydration 2913.3.3 Thermodynamics 2914. Conclusions 2955. Acknowledgements 2986. References 298In recent years the availability of large quantities of pure synthetic DNA and RNA has
revolutionised the study of nucleic acids, such that it is now possible to study their
conformations, dynamics and large-scale properties, and their interactions with small ligands,
proteins and other nucleic acids in unprecedented detail. This has led to the (re)discovery of
higher order structures such as triple helices and quartets, and also the catalytic activity of
RNA contingent on three-dimensional folding, and the extraordinary specificity possible with
DNA and RNA aptamers.Nucleic acids are quite different from proteins, even though they are both linear polymers
formed from a small number of monomeric units. The major difference reflects the nature of
the linkage between the monomers. The 5′–3′ phosphodiester linkage in nucleic acids carries
a permanent negative charge, and affords a relatively large number of degrees of freedom,
whereas the essentially rigid planar peptide linkage in proteins is neutral and provides only
two degrees of torsional freedom per backbone residue. These two properties conspire to
make nucleic acids relatively flexible and less likely to form extensive folded structures. Even
when true 3D folded structures are formed from nucleic acids, the topology remains simple,
with the anionic phosphates forming the surface of the molecule. Nevertheless, nucleic acids
do occur in a variety of structures that includes single strands and high-order duplex, triplex
or tetraplex (‘quadruplex’) forms. The principles of biological recognition and the related
problem of understanding the forces that stabilise such folded structures are in some respects
more straightforward than for proteins, making them attractive model systems for
understanding general biophysical problems. This view is aided by the relatively facile
chemical synthesis of pure nucleic acids of any desired size and defined sequence, and the ease
of incorporation of a wide spectrum of chemically modified bases, sugars and backbone
linkers. Such modifications are considerably more difficult to achieve with oligopeptides or
proteins.
The structural plasticity of nucleic acid duplexes revealed by WAXS and MD
