Libraries of randomized RNA will be synthesized for use in the SELEX procedure. High-affinity ligands to the RNase H domain of HIV-1 RT will be isolated. The essential information at the nucleotide level will be determined from this collection of ligands by computer and experimental methods. We will study the effects on binding affinity of chemical modification and nucleotide adduct substitution. Three-dimensional structure determination on model ligands complexed with target protein will yield atomic resolution of the essential features of the RNA-protein interaction. through such efforts, rational modifications of the nucleic acid ligands will lead to first generation therapeutics or serve as models for mimetic therapeutics for AIDS patients.