STRUCTURE AND FUNCTION OF NUCLEIC ACIDS

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The long term goal is to be able to deduce a three-dimensional structure for an RNA molecule from the sequence of its bases. Messenger RNA molecules transfer and interpret the genetic information in DNA to produce proteins. Ribosomal RNAs and transfer RNAs are part of the machinery necessary to synthesize the proteins. Errors in RNA processing, in control of messenger RNA translation, and in control of messenger RNA lifetimes are linked to many human diseases, including several neurodegenerative diseases such as Lou Gehrig's disease. In RNA viruses the RNA is both the genetic information, and the messenger for protein synthesis. Thus, naturally occurring RNAs and viral RNAs are outstanding targets for drugs to prevent or cure disease. The overwhelming majority of drug targets up to now have been proteins. Knowledge of the three-dimensional structures of RNAs is crucial to understanding RNA function. The RNA molecules are synthesized in the laboratory by RNA polymerase from a DNA template, using 13C and 15N isotope labeling, if needed. Multidimensional nuclear magnetic resonance spectroscopy of the RNA molecules provides distances between protons, and torsion angles around bonds. Standard bond angles and bond lengths, plus the NMR experimental distances and angles, are used in molecular dynamics simulations to obtain coordinates for each atom in the RNA molecule. Representative structural motifs that occur in RNAs are being determined. The thermodynamic stabilities of these motifs (secondary and tertiary structures) relative to the single-stranded molecules are assessed from measured equilibrium concentrations of the different species. This information will lead to improved prediction of RNA structure from sequence alone. RNA structures will help in understanding function, and in controlling the RNA role in viral and genetic diseases.