The sequence specific recognition of double helical DNA is an essential biological process responsible for the regulation of cellular functions including transcription, replication, and cell division. The ability to design synthetic molecules that bind sequence specifically to unique sites on human DNA has major implications for the treatment of genetic, oncogenic and viral diseases. Basic research on structure-function issues such as recognition and covalent modification of DNA will be carried out. Research will focus on recognition of the minor groove of double helical DNA by a novel 2:1 peptide:DNA motif. Our specific objectives during the next four years are: (1) develop solid phase methods for the synthesis of oligopeptides containing imidazole and N-methylpyrrolecarboxamides. (2) define the sequence composition rules for recognition for the 2:1 peptide DNA motif by constructing and studying of the energetics of twenty-six different hairpin peptides. (3) define the upper limits for binding site size by the 2:1 motif. (4) design and study the energetics of binding of a novel class of alpha-amino acid linked imidazole-methylpyrrolecarboxamide peptides. (5) synthesize a class of rigid hairpin peptides and analyze the energetics for affinity and specificity. (6) synthesize a class of cyclic peptides and analyze the energetics for affinity and specificity. (7) develop a method for sequence specific DNA bending by the 2:1 DNA motif. (8) develop sequence specific ligation of double helical DNA promoted by minor groove binding prptides. In addition to the synthesis, specificity, and energetic studies at Caltech, all new synthetic peptides will be sent to UC Berkeley for structure elucidation of the peptide-DNA complexes by 2-D NMR.
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