The Importance of Phosphates for DNA G-Quadruplex Formation: Evaluation of Zwitterionic G-Rich Oligodeoxynucleotides

Yongdong Su, Patrick J.B. Edwards, Dmitry A. Stetsenko, Vyacheslav V. Filichev

Research output: Contribution to journalArticlepeer-review

1 Citation (Scopus)

Abstract

A quaternary ammonium butylsulfonyl phosphoramidate group (N+) was designed to replace all the phosphates in a G-rich oligodeoxynucleotide d(TG4T), resulting in a formally charge-neutral zwitterionic N+TG4T sequence. We evaluated the effects of N+phosphate modifications on the structural, thermodynamic and kinetic properties of the parallel G-quadruplexes (G4) formed by TG4T and compared them to the properties of the recently published phosphoryl guanidine d(TG4T) (PG-TG4T). Using size-exclusion chromatography, we established that, unlike PG-TG4T, which exists as a mixture of complexes of different molecularity in solution, N+TG4T forms an individual tetramolecular complex. In contrast to PG modifications that destabilized G4s, the presence of N+ modifications increased thermal stability relative to unmodified [d(TG4T)]4. The initial stage of assembly of N+TG4T proceeded faster in the presence of Na+ than K+ions and, similarly to PG-TG4T, was independent of the salt concentration. However, after complex formation exceeded 75 %, N+TG4T in solution with Na+showed slower association than with K+. N+TG4T could also form G4s in solution with Li+ions at a very low strand concentration (10 μM); something that has never been reported for the native d(TG4T). Charge-neutral PG-G4s can invade preformed native G4s, whereas no invasion was observed between N+and native G4s, possibly due to the increased thermal stability of [N+TG4T]4. The N+ modification makes d(TG4T) fully resistant to enzymatic digestion, which could be useful for intracellular application of N+-modified DNA or RNA.

Original languageEnglish
Pages (from-to)2455-2466
Number of pages12
JournalChemBioChem
Volume21
Issue number17
DOIs
Publication statusPublished - 1 Sep 2020

Keywords

  • DNA
  • enzymatic stability
  • G-quadruplexes
  • kinetics
  • modified phosphate
  • thermal stability
  • MOTIFS
  • PNA
  • STABILITY
  • CD SPECTRA
  • COMPLEMENTARY
  • GUANOSINE-QUARTET STRUCTURE
  • KINETICS
  • SEQUENCE
  • LOCKED NUCLEIC-ACIDS
  • BINDING

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