2D-IR spectroscopy shows that optimised DNA minor groove binding of Hoechst33258 follows an induced fit model

Lennart A. I. Ramakers, Gordon Hithell, John J. May, Gregory M. Greetham, Paul M. Donaldson, Michael Towrie, Anthony W. Parker, Glenn Burley, Neil Hunt

Research output: Contribution to journalArticle

16 Citations (Scopus)
39 Downloads (Pure)

Abstract

The induced fit binding model describes a conformational change occurring when a small molecule binds to its biomacromolecular target. The result is enhanced non-covalent interactions between ligand and biomolecule. Induced fit is well-established for small molecule-protein interactions, but its relevance to small molecule-DNA binding is less clear. We investigate the molecular determinants of Hoechst33258 binding to its preferred A-tract sequence relative to a sub-optimal alternating A-T sequence. Results from 2-dimensional infrared spectroscopy, which is sensitive to H-bonding and molecular structure changes, show that Hoechst33258 binding results in loss of minor groove spine of hydration in both sequences, but an additional perturbation of the base propeller twists occurs in the A-tract binding region. This induced fit maximizes favourable ligand-DNA enthalpic contributions in the optimal binding case and demonstrates that controlling the molecular details that induce subtle changes in DNA structure may hold the key to designing next-generation DNA-binding molecules.
Original languageEnglish
JournalJournal of Physical Chemistry B
Early online date19 Jan 2017
DOIs
Publication statusE-pub ahead of print - 19 Jan 2017

Keywords

  • spectroscopy
  • DNA
  • Hoechst33258
  • minor groove binding
  • induced fit
  • non-covalent interactions
  • ligand
  • biomolecule
  • molecule-DNA binding

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