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Thermodynamics of nucleic acids and their interactions with ligands

  • Andrew N. Lane (a1) and Terence C. Jenkins (a2)

Abstract

1. Introduction 255

1.1 General thermodynamics 256

2. Nucleic acid thermodynamics 260

2.1 DNA duplexes 261

2.2 RNA duplexes 263

2.3 Hybrid DNA–RNA duplexes 264

2.4 Hydration 267

2.5 Conformational flexibility 269

2.6 Thermodynamics 272

3. Nucleic acid–ligand interactions 277

3.1 Minor groove binders 278

3.2 DNA intercalators 284

3.3 Triple-helical systems 288

3.3.1 Structures 288

3.3.2 Hydration 291

3.3.3 Thermodynamics 291

4. Conclusions 295

5. Acknowledgements 298

6. References 298

In 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.

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Corresponding author

Corresponding author: Division of Molecular Structure, National Institute for Medical Research, The Ridgeway, Mill Hill, London NW7 1AA, UK

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