Recognition of guanine-guanine mismatches by the dimeric form of 2-amino-1,8-naphthyridine

J Am Chem Soc. 2001 Dec 19;123(50):12650-7. doi: 10.1021/ja0109186.

Abstract

Dimeric 2-amino-1,8-naphthyridine selectively binds to a G-G mismatch with high affinity (K(d) = 53 nM). We have investigated a binding mechanism of naphthyridine dimer 2 to a G-G mismatch by spectroscopic studies, thermodynamic analysis, and structure-activity studies for the thermal stabilization of the mismatch. 1H NMR spectra of a complex of 2 with 9-mer duplex d(CATCGGATG)2 containing a G-G mismatch showed that all hydrogens in two naphthyridine rings of 2 were observed upfield compared to those of 2 in a free state. The 2D-NOESY experiments showed that each naphthyridine of 2 binds to a guanine in the G-G mismatch within the pi-stack. In CD spectra, a large conformational change of the G-G mismatch-containing duplex was observed upon complex formation with 2. Isothermal calorimetry titration of 2 binding to the G-G mismatch showed that the stoichiometry for the binding is about 1:1 and that the binding is enthalpy-controlled. It is clarified by structure-activity studies that show (i) the linker connecting two naphthyridine rings was essential for the stabilization of the G-G mismatch, (ii) the binding efficiency was very sensitive to the linker structure, and (iii) the binding of two naphthyridines to each one of two Gs in the G-G mismatch is essential for a strong stabilization. These results strongly supported the intercalation of both naphthyridine rings of 2 into DNA base pairs and the formation of a hydrogen bonded complex with the G-G mismatch.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Base Pair Mismatch*
  • Circular Dichroism
  • DNA / chemistry*
  • Dimerization
  • Guanine / chemistry*
  • Hydrogen Bonding
  • Naphthyridines / chemical synthesis
  • Naphthyridines / chemistry*
  • Nuclear Magnetic Resonance, Biomolecular
  • Nucleic Acid Conformation
  • Structure-Activity Relationship
  • Thermodynamics

Substances

  • 2-amino-1,8-naphthyridine
  • Naphthyridines
  • Guanine
  • DNA