The thermodynamics of drug-dna interactions: Ethidium bromide and propidium iodide

Wan Yin Chou, Luis A. Marky, Denise Zaunczkowski, Kenneth J. Breslauer

Research output: Contribution to journalArticle

63 Scopus citations

Abstract

We report the first calorimetrically-derived characterization of the thermodynamics of ethidium bromide (EB) and propidium iodide (PI) binding to a series of nucleic acid host duplexes. Our spectroscopic and calorimetric measurements yield the following results: 1) At low salt (16mM Na+) and 25°C, PI binds more strongly than EB to a given host duplex. The magnitude of this PI preference depends only marginally on base sequence, with AT base pairs showing a greater PI preference than GC base pairs. 2) The enhanced binding of PI relative to EB at low salt and 25°C reflects a more favorable entropic driving force for PI binding. 3) The PI binding preference diminishes at higher salt concentrations (216mM). In other words, the binding preference is electrostatic in origin. 4) The salt dependence of the binding constants (∂lnKb/∂ln[Na+]) reveal that PI binds as a dication while EB binds as a monocation. 5) PI and EB both exhibit impressive enthalpy-entropy compensations when they bind to the deoxy homopolymers poly dA poly dT and poly dA poly dU. We have observed a similar enthalpy-entropy compensation for netropsin binding to the poly dA poly dT homopolymer duplex. We therefore conclude that the compensation phenomenon is an intrinsic property of the host duplex rather than reflecting a property of the binding ligand. 6) When either PI or EB bind to the corresponding ribo homopolymer (poly rA poy rU) we do not observe the enthalpy-entropy compensation that characterizes the binding to the deoxy homopolymer. 7) EB and PI both bind more strongly to poly d(AT) o poly d(AT) than to poly d(AU) o poly d(AU). Specifically, the absence of the thymine methyl group in poly d(AU) poly d(AU) reduces the binding constant of both drugs by a factor of four. This reduction in binding is due to a less favorable entropy change.

Original languageEnglish (US)
Pages (from-to)345-362
Number of pages18
JournalJournal of Biomolecular Structure and Dynamics
Volume5
Issue number2
DOIs
StatePublished - Oct 1987

ASJC Scopus subject areas

  • Structural Biology
  • Molecular Biology

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