Structural Basis of DNA Recognition by Synthetic Ligands

The DNA double helix presents functional groups in the major and minor grooves that can be used by ligands for readout of the base pair sequence. The overall flexibility and shape also distinguishes various sequences. Although the information displayed in the major groove is more diverse, small DNA-binding polyamides predictably distinguish all four base pairs in the minor groove. In this work, the structural basis of this recognition has been studied using x-ray crystallographic techniques, and is described for G•C (Chapter 2) and T•A base pairs (Chapter 3-4). The polyamides directly read the DNA sequence using a combination of specific hydrogen bonds and shape selection. A second class of ligands called intercalators bind to DNA via the major groove by slipping a planar aromatic ligand between the bases. Although this shape-selective DNA binding is relatively nonspecific, the substitution of the ancillary ligands on octahedral metallointercalators allows specific sequences to be recognized in the major groove. The high resolution crystal structure of a designed metal complex bound to its target site reveals the nature of these specific contacts, as well as the precise stacking of the ligand between the bases. A detailed understanding of specific DNA recognition by small molecules is important for their further development as tools for molecular biology and medicine. These structures reveal how synthetic ligands can distinguish all four base pairs in both the major and the minor grooves of DNA