The objectives of the proposed research are to determine the detailed structure [and to decipher the sequence-dependence of the structure] of double helical nucleic acids containing both RNA and DNA in the same duplex. Major emphasis will be placed on the sequence dependence of the structure of RNA:DNA hybrid duplexes and on covalent chimeric duplexes containing hybrid segments joined to DNA segments as well as hybrid segments joined to RNA segments. Such chimeric duplexes are extremely important in biology in such processes as the initiation of DNA synthesis, the continued replication of DNA, and the growth of retroviruses - yet little is known of their detailed structure and the importance of sequence on their function. We have recently demonstrated that many current ideas concerning the structure of hybrid duplexes and hybrid duplex junctions are very likely to be crystallographic artifacts. Hence all of the proposed structural studies will be carried out in solution using high-resolution NMR spectroscopy. These biologically important structures determined directly in solution will have widespread importance not only in modern molecular biology but will also generate new targets for specifically inhibiting the life-cycle of retroviruses.
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