Structural characterization of a guanine-quadruplex ligand complex

Biochemistry. 2000 Nov 7;39(44):13422-32. doi: 10.1021/bi001584k.

Abstract

The inhibition of telomerase by molecules such as disubstituted amidoanthraquinones is believed to be due to their stabilization of guanine-quadruplex complexes. The characterization is reported of a complex with the intermolecular parallel quadruplex formed from the sequence TGGGGT and a 1,4-bis-piperidino amidoanthraquinone. Crystals obtained did not give single-crystal diffraction; the fiber-like pattern has been interpreted in terms of a repeating unit with four guanine-quartets and two stacked/intercalated ligand molecules. The two categories of possible structures for the complex consistent with this interpretation have been examined by molecular dynamics simulations, with fully solvated environments and 1000 ps simulation times. The two central guanine-quartets in the intercalation model rapidly became highly distorted, whereas the two types of models with ligand stacked externally on the ends of the quadruplex remained very stable. It was concluded that the externally bound ligand complexes best represent the structure of this quadruplex complex, in agreement with earlier NMR results on related systems.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Anthraquinones / chemistry
  • Computer Simulation
  • Crystallization
  • DNA / chemistry*
  • Enzyme Inhibitors / chemistry
  • G-Quadruplexes
  • Guanine / chemistry*
  • Hydrogen Bonding
  • Intercalating Agents / chemistry
  • Ligands
  • Models, Molecular
  • Nucleic Acid Conformation*
  • Oligonucleotides / chemistry
  • Structure-Activity Relationship
  • Telomerase / antagonists & inhibitors
  • Templates, Genetic
  • X-Ray Diffraction

Substances

  • Anthraquinones
  • Enzyme Inhibitors
  • Intercalating Agents
  • Ligands
  • Oligonucleotides
  • 1-piperidinoanthraquinone
  • Guanine
  • DNA
  • Telomerase