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

Research output: Contribution to journalArticle

Author(s)

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

Department/unit(s)

Publication details

JournalJournal of Physical Chemistry B
DatePublished - 19 Jan 2017
Issue number6
Volume121
Number of pages9
Pages (from-to)1295-1303
Original languageEnglish

Abstract

The induced fit binding model describes a conformational change occurring when a small molecule binds to its biomacromolecular target. The result is enhanced noncovalent interactions between the 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 suboptimal alternating A-T sequence. Results from two-dimensional infrared spectroscopy, which is sensitive to H-bonding and molecular structure changes, show that Hoechst33258 binding results in loss of the 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 favorable 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.

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