Groove Binding

The DNA helix has two grooves of different size, the minor and major grooves, which can serve as binding sites for guest molecules. Whereas relatively large molecules such as proteins bind preferentially to the major

Fig. B.9.1. Molecules such as organic dyes, polycyclic aromatic compounds, organometallic complexes, saccharides, peptides, and polyamides bind to nucleic acids. Two major binding modes are possible - intercalation (left) and groove binding (right).

groove of DNA [1], the minor groove is the preferred binding site for small ligands [2, 3]. The binding pocket of a DNA groove can be defined by two different regions, the "bottom", formed by the edges of the nucleic bases that face into the groove, and the "walls", which are formed from the deoxyribose phosphate backbone of the DNA. Groove binders usually comprise at least two aromatic or heteroaromatic rings the connection of which enables conformational flexibility such that a crescent-shaped conformation can be achieved and the molecule fits perfectly into the groove. In addition, functional groups are required to form hydrogen bonds with the nucleic bases at the bottom of the groove. A typical minor-groove binder is Hoechst 33258 (shown to the right in Figure B.9.1). Most groove binders have binding selectivity towards AT-rich areas, because grooves which consist of GC base pairs are sterically hindered by the guanine amino functionality at C-2 and its hydrogen bond with the C-2 carbonyl functionality of cytosine. It has also been observed that in AT-rich grooves the electrostatic potential is larger than in GC-rich regions. Thus, positively polarized or charged ligands also have higher affinity for the AT-rich groove because of favorable electrostatic attraction. Despite these considerations groove binders are known that bind preferentially in GC-rich grooves, because they are substituted with functionality that forms strong attractive interactions with the guanine amino group [4].

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