Poster abstracts

Poster number 27 submitted by Maximillian Bailor

Combination of Chemical Shift and Residual Dipolar Coupling Perturbations Reveals Structural Differences Among Related Aminoglycosides Bound to the Same RNA Target

Maximillian H. Bailor (Dept Chemistry at the University of Michigan), Hashim M. Al-Hashimi (Departments of Chemistry & Biophysics)

Abstract:
Chemical shift perturbations occupy an important facet in the study of biological molecules by nuclear magnetic resonance (NMR) spectroscopy. Given the complexity of their interpretation, however, they are often used as a rudimentary means to measure dissociation constants or to determine the relative binding site of a drug. Residual dipolar couplings (RDCs) on the other hand represent a sensitive technique which is un-obscured by the complexity that plagues chemical shifts and demonstrates a particularly useful method by which one may acquire structural data. By combining the chemically sensitivity nature of chemical shift perturbations with the structural sensitivity of RDCs we have been able to more completely characterize binding modes of aminoglycosides to RNA. In particular, the strategy yields a description of RNA binding sites and RNA structural changes that follow recognition. Especially when considering the malleability of RNA and the structural flexibility of the drugs they encounter, such analyses of conformational adaptation is key for successful interpretation of structure-activity relationships. Using this approach, we have uncovered an unprecedented degree of structural adaptability accompanying the recognition of HIV-1 TAR RNA by structurally related aminolgycosides. We show that even the chemically similar Neomycin B (NeoB), Ribostamycin (Rib), and Kanamycin B (KanB) bind to very different conformational manifestations of the TAR RNA target. Our results suggest that even minimal structural differences can result in significant global and local changes to the RNA

Keywords: TAR, Aminoglycosides, Residual Dipolar Couplings