STRUCTURAL AND DYNAMIC ASPECTS OF DRUG/DNA INTERACTIONS

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DESCRIPTION: The goal of this project is to continue to improve understanding of ligands which interact with DNA in a sequence specific manner, and to improve the design of such molecules. Ligands designed to target any particular DNA sequence with both high affinity and specificity would be very useful in biochemistry and molecular biology, and also potentially as therapeutic agents. the investigator's focus has been derivatives of the natural product distamycin, containing three pyrrole rings, which has a preference for binding in the minor groove at sequences containing four sequential A,T pairs. He has demonstrated that synthetic derivatives containing imidazole rings bind selectively at specific sequences containing both A,T and G,C pairs, utilizing hydrogen bonding to recognize the amino group of guanosine in the minor groove. Different combinations of these 'recognition modules' have been demonstrated to bind specifically at a number of different DNA sequences, including mostly G,C pairs. Linking such modules has allowed recognition of sites up to 13 base pairs in long. Work proposed will extend studies of linked ligands for recognition of general, mixed A,T and G,C sequences. Linking different recognition modules for enhancing specificity in binding has been shown, and good linkers have been found. For some binding modes the linkers affect the binding affinity and specificity. Dr. Wemmer will study several linked ligand complexes by NMR to understand the interactions with DNA, which will allow development of optimal designs. Linkers for hairpin complexes and extended complexes, with the linker partially controlling the preferred binding mode, and inflexible extensions will be examined. A particularly important area in the next period will be to better understand the factors which control specificity in binding of these designed ligands. The ligands which have been designed do in fact bind with significant preference for the selected target sites. However, there is a substantial range of discrimination between correct and incorrect or mismatched sites. The problem of discrimination seems to increase as the number of G:C pairs in the target site increases. Dr. Wemmer has two challenges, first to understand the origin of these effects, and second to control them. Meeting these challenges will also require developing new methods for determining the specificity for ligands which recognize long target sequences. A final area of work will be to link the minor groove binding agents to other molecules which can be used for sensitive detection, or to carry out chemistry on the target DNA.