• Structure/function relationships of nucleic acids
• Roles of modified nucleosides in tRNA
• Introduction of modified nucleosides into RNA and DNA
• Nuclear magnetic resonance (NMR) of RNA
• RNA:RNA and RNA:protien interactions
• RNA-based drug therapeutics
RNA, the macromolecule central to the control and expression of genes, is the new target of disease intervention, and a macromolecular tool relevant to all of biology. We are interested in the structure-function relationship of RNAs, including the design of new RNAs. Particularly, we investigate how the structure and chemistry of RNA allows it to function in protein synthesis, in the replication of HIV, and in control of genes in pathogenic bacteria. To do this we utilize nuclear magnetic resonance (NMR) and other biophysical methods, as well as biochemical, molecular, and chemical techniques.
Structure-function relationships of nucleic acids, such as that of tRNA in protein synthesis, are fundamental to all cell and molecular biology. In order to probe the structure-function relationships of RNAs as potential targets or tools, we have developed methods for the introduction of native, non-natural, and stable isotope labeled nucleosides. We have found that modified nucleosides in tRNA play an important structural and functional role both within the tRNA molecules and in tRNA anticodon recognition of select codons at the wobble position. Modified nucleosides alter codon "wobble," enhance ribosome binding, explain programmed translational frameshifting, are determinants for aminoacyl-tRNA synthetase recognition, and are involved in human immunodeficiency virus (HIV) selection of a specific human tRNA to prime reverse transcription.
Our studies of tRNA and other RNAs utilize molecular genetic, microbiological, biochemical and chemical and biophysical methods to more clearly and precisely define the site-specific structure-function relationships and design new nucleic acids. For instance, many aspects of tRNA structure have now been found to exist in DNA. Our technologies have permitted us to design a DNA analog to an RNA, and for that DNA to have the same function as the RNA in protein synthesis. The newly designed DNA prevents native tRNA from binding the ribosome. Other DNAs we have designed block aminoacylation of tRNA and posttranslational modification of tRNA.