ABSTRACT
The DNA molecule, that icon of molecular biology which has been adopted to serve almost as an icon of modern biology in general, is a very special structure from the standpoint of molecular recognition. Because it is the ultimate repository of genetic information in living things, unicellular as well as multicellular organisms, its essentially linear array of genes encoded in an immensely long sequence of nucleotides represents a unique vehicle for chemical recognition to modulate biological function and affords a vital target for medical intervention. To put the issue in a nutshell, interactions with DNA which are directed at recognising specific portions of its sequence of base pairs have the potential to extract from DNA its raison d’être ultimately eliciting a biological response. Elsewhere in this volume will be found numerous examples of biotechnological applications and goals where the capability to identify, react with, or even modify the nucleotide sequence of DNA furnishes the fundamental chemistry to achieve something useful. Here we confine ourselves to a consideration of the principles upon which sequence recognition may be based, illustrated with examples which serve to focus discussion of issues that will receive more substantial treatment later. In this chapter, we propose to adopt a special framework upon which to hang our discussion of structural aspects of the DNA recognition process. We will view DNA interactions along a spectrum from recognition by shape and other secondary structural features (analogue), to direct sequence readout (digital). The distinction between these two extreme modalities of perceiving sequence information is valid for other macromolecules too, of course, but the elegance of the concept is particularly striking as it applies to DNA. While the ligands referred to are by no means an exhaustive compilation, most examples selected to illustrate the various modes of interaction with DNA will be chosen from a diverse set of small drug-like molecules, though we do not hesitate to enlist large macromolecules when appropriate. But first, to understand DNA interactions and the fundamental basis for recognition processes, it behoves us to look at the DNA receptor itself in order to visualise those features of its structure that allow for recognition.
