Faculty

Our laboratory applies solution state NMR spectroscopy to investigate the molecular basis of RNA function in processes ranging from gene expression (e.g. transcriptional activation and translation) to virion functioning (e.g. genome packaging and reverse transcription). We make extensive use of new NMR techniques involving measurements of residual dipolar couplings in determining global aspects of RNA structure, dynamics and interaction.

Although much of our understanding about RNA function comes from analyses of ground-state conformations, structurally distinct excited states accessible through molecular dynamics are frequently the ones carrying out catalysis and undergoing recognition. A central goal of our laboratory is to develop and apply NMR techniques for determining high-resolution RNA structures as a function of time and other reaction coordinates. Research involves biochemical preparation/purification of isotopically labeled RNA samples, design of NMR experiments, and development of theoretical frameworks for analyzing data. Specific areas of interests include the Mg2+ induced folding trajectory of the 56-nucleotide P5abc subdomain of the Tetrahymena group I ribozyme important for catalysis, and symmetrical dimerization of homologous genomic RNA strands important for HIV-1 viral replication. In another area, and as part of a multi-institutional RNA structural genomics program, we are developing approaches for high throughput RNA structure determination. These advances will enable large-scale systematic studies of RNA structure-function relationship in areas ranging from evolution to structure assisted design of therapeutics.

We are principal users of 600 MHz and 800 MHz spectrometers, soon to be equipped with cryogenic probes, and have access to the Michigan Life Sciences Corridor 900 MHz NMR facility. The lab is well equipped to carry out biochemical, biophysical and computational investigations.

Representative Publications

1. Al-Hashimi, H.M., Gorin, A., Majumdar, A., Gosser, Y. and Patel, D.J., "Towards Structural Genomics of RNA: Rapid NMR Resonance Assignment and Simultanous RNA Tertiary Structure Determination using Residual Dipolar Couplings", J. Mol. Biol., 2002, 318, 637.

2. Al-Hashimi, H. M. et al, "Concerted Motions in HIV-1 TAR RNA may Allow Access to Bound State Conformations: RNA Dynamics from NMR Residual Dipolar Couplings", J. Mol. Biol., 2002, 315, 95.

3. Al-Hashimi, H. M., Tolman, J. R., Majumdar, A., Gorin, A. and Patel, D. J., "Determining Stoichiometry in Homomultimeric Nucleic Acid Complexes using Magnetic Field Induced Residual Dipolar Couplings", J. Am. Chem. Soc., 2001, 123, 5806.

4. Al-Hashimi, H. M. et al, "Field- and Phage-Induced Dipolar Couplings in a Homodimeric DNA Quadruplex, Relative Orientation of G Center Dot(C-A) Triad and G-tetrad Motifs and Direct Determination of C2 Symmetry Axis Orientation", J. Am. Chem. Soc., 2001, 123, 633.

5. Al-Hashimi, H. M. et al, "Variation of Molecular Alignment as a Means of Resolving Orientational Ambiguities in Protein Structures from Dipolar Couplings", J. Magn. Reson., 2000, 143, 402.