title: Sheared Aanti.Aanti base pairs in a destabilizing 2 x 2 internal loop: the NMR structure of 5'(rGGCAAGCCU)2.
abstract: The 5'(rGGCAAGCCU)(2) duplex contains tandem A.A pairs. The three-dimensional structure of the 5'(rGGCAAGCCU)(2) duplex was modeled by molecular dynamics and energy minimization with NMR-derived distance and dihedral angle restraints. Although the 5'(rCAAG)(2) loop is thermodynamically destabilizing by 1.1 kcal/mol, the tandem A.A pairs adopt a predominant conformation: a sheared anti-anti (A.A trans Hoogsteen/Sugar-edge) alignment similar to that observed in the crystal structure of the P4-P6 domain of the Tetrahymena thermophila intron [Cate, J. H., Gooding, A. R., Podell, E., Zhou, K., Golden, B. L., Kundrot, C. E., Cech, T. R., and Doudna, J. A. (1996) Science 273, 1678-1685]. The NMR-derived structure of the 5'(rGGCAAGCCU)(2) duplex exhibits cross-strand hydrogen bonds from N3 of A4 to an amino hydrogen of A5 and from the 2' oxygen of the A4 sugar to the other amino hydrogen of A5. An intrastrand hydrogen bond is formed from the 2' OH hydrogen of A4 to O5' of A5. The cross-strand A5 bases are stacked. The Watson-Crick G-C regions are essentially A-form. The sheared anti-anti (A.A trans Hoogsteen/Sugar-edge) alignment provides potential contact sites for tertiary interactions and, therefore, is a possible target site for therapeutics. Thus, thermodynamically destabilizing internal loops can be preorganized for tertiary interactions or ligand binding.
authors.affiliation: Department of Chemistry, University of Rochester, New York 14627-0216, USA.
authors.forename: Brent M
authors.initials: BM
authors.lastname: Znosko
authors.forename: Mark E
authors.initials: ME
authors.lastname: Burkard
authors.forename: Susan J
authors.initials: SJ
authors.lastname: Schroeder
authors.forename: Thomas R
authors.initials: TR
authors.lastname: Krugh
authors.forename: Douglas H
authors.initials: DH
authors.lastname: Turner
mesh_terms: D000241:Adenosine / Q000737:chemistry*; D000818:Animals; D020029:Base Pairing; D018360:Crystallography, X-Ray; D003853:Deoxyribonucleosides / Q000737:chemistry*; D019906:Nuclear Magnetic Resonance, Biomolecular / Q000379:methods; D009690:Nucleic Acid Conformation; D009692:Nucleic Acid Heteroduplexes / Q000737:chemistry*; D010759:Phosphorus Isotopes / Q000737:chemistry; D011522:Protons; D016053:RNA, Protozoan / Q000737:chemistry; D013329:Structure-Activity Relationship; D016808:Tetrahymena thermophila; D013816:Thermodynamics
chemical_list: D003853:Deoxyribonucleosides; D009692:Nucleic Acid Heteroduplexes; D010759:Phosphorus Isotopes; D011522:Protons; D016053:RNA, Protozoan; D000241:Adenosine