Intrastrand base-stacking buttresses widening of major groove in interstrand cross-linked B-DNA

Mateus Webba Da Silva, Ross G. Bierbryer, Christopher J. Wilds, Anne M. Noronha, O. Michael Colvin, Paul S. Miller, Michael P. Gamcsik

Research output: Contribution to journalArticlepeer-review

6 Scopus citations


The introduction of a covalent interstrand cross-link induces changes in the intrinsic structure and deformability of the DNA helix that are recognized by elements of the DNA repair apparatus. In this context, the solution structure of the undecamer d(CGAAAT*TTTCG)2, where T* represents a N3T-butyl-N3T interstrand cross-link, was determined using molecular dynamics calculations restrained by NOE and dihedral angle data obtained from NMR spectroscopy. The structure of this cross-linked undecamer shows dramatic widening of the major groove of the B-DNA stem without disruption of Watson-Crick base pairing. This change in tertiary structure illustrates the cumulative effect of cooperativity in intrastrand base stacking of an A-tract of three adenines. Further, it is the direct result from the imposition of geometric angular constraints by the cross-link chain on an ApT* and T*pT steps in the segment AAAT*T. The widening of the major groove is due to the dominant contribution of base stacking to the stability of the ApT compared to the TpT step suggesting that the latter is more deformable within a DNA stem. Compared to earlier structures of ethyl cross-linked oligonucleotides, this unique perturbation induced by the butyl moiety offers a new probe for systematic studies of DNA repair mechanisms.

Original languageEnglish (US)
Pages (from-to)4580-4587
Number of pages8
JournalBioorganic and Medicinal Chemistry
Issue number14
StatePublished - Jul 15 2005


  • DNA Interstrand crosslinks
  • DNA repair
  • Solution NMR structure

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Medicine
  • Molecular Biology
  • Pharmaceutical Science
  • Drug Discovery
  • Clinical Biochemistry
  • Organic Chemistry


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