STRUCTURE AND FUNCTION OF NUCLEIC ACIDS

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The long-term goal is to be able to use the sequence of a DNA or RNA to predict its three dimensional structure in its natural cellular or extracellular environment. As structure implies function, one can then understand and learn to control its biological function. The synthesis of every protein is specified by a messenger RNA. The messenger RNA is produced by processing a primary transcript transcribed from DNA. The specific folded conformations of these nucleic acids are essential for their correct function. Replication of RNA viruses and DNA viruses requires synthesis of RNA molecules. Thus, knowledge of the sequence and folding of a pathogenic viral RNA can reveal methods for preventing viral replication, and curing or preventing the viral disease. Genetic diseases and autosomal genetic diseases, such as cancer, are caused by a change in sequence of DNA. It is vital to understand how the changes in sequence can occur, and what the effects of these changes are on the replication and transcription of the DNA, and on the processing and translation of the RNA. The relation between nucleic acid sequence and conformation, and its role in protein sequence is central to many problems of human health. Oligonucleotides will be synthesized that can form important structural motifs present in RNA and DNA. Their sequences and their environments will be varied to determine what structures do form and what conditions are required for their formation. Reactivity of the oligonucleotides to enzymes and to chemical reagents will reveal double strand and single strand regions. Spectroscopic measurements, conformations. Thermodynamic parameters which characterize the stabilities of the different motifs will exchange between different conformations will be determined by NMR, or by temperature-jump methods. The structural elements to be studied in RNA include pseudoknots, hairpin loops, base-base mismatches, internal loops, bulges, and left-handed Z-RNA. In DNA the motifs include base-base mismatches, telomeric sequences, and two-, three- and four-stranded complexes involving guanine base pairs.