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The Origins of the DNA Binding Affinity and Specificity of Minor Groove Directed Ligands: Correlations of Thermodynamic and Structural Data

Breslauer, Kenneth J. and Ferrante, Robert and Marky, Luis A. and Dervan, Peter B. and Youngquist, R. Scott (1990) The Origins of the DNA Binding Affinity and Specificity of Minor Groove Directed Ligands: Correlations of Thermodynamic and Structural Data. In: Structure and Methods. Vol.2. Adenine Press , pp. 273-289. ISBN 0-940030-22-5.

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We report complete thermodynamic binding profiles for the complexation of three minor groove directed ligands [netropsin. P2 (a synthetic analogue of netropsin), and distamycin A] to selected DNA host duplexes. From a comparison of the DNA binding profiles associated with these ligands, we are able to reach the following conclusions: 1) The minor groove binding of each ligand is overwhelmingly enthalpy-driven and exhibits a very high binding affinity (K-109 at 25°C). 2) The thermodynamic binding data primarily reflect local ligand-DNA interactions rather than long-range binding-induced conformational changes at regions distant from the binding site. 3) Deep penetration into the minor groove is required to form those ligand-DNA interactions responsible for the enthalpy-driven high binding affinity. 4) IC base pairs form min or groove binding sites for these ligands that thermodynamically are equivalent to those formed by AT base pairs. 5) The enhanced binding affinity associated with deep penetration of the ligands into the minor groove does not result from more favorable electrostatic interactions. 6) Removal of one of the two charged ends of a ligand (P2 versus netropsin) results in a reduction in binding affinity at 25°C that is entirely entropic in origin. 7) The pyrrole/carboxamide bodies of these ligands rather than the charged-ends form the ligand interactions with the minor groove of DNA that give rise to the observed enthalpy driven high binding affinity. We propose correlations between our thermodynamic data and specific molecular interactions defined by x-ray and NMR structural studies on similar and identical drug-DNA complexes. These correlations illustrate the power of parallel structural and thermodynamic studies for developing a microscopic understanding of macroscopic data.

Item Type:Book Section
Dervan, Peter B.0000-0001-8852-7306
Additional Information:© 1990 Adenine Press. This research was supported by grants GM23509 (KJB), GM34469 (KJB), and GM27681 (PBD).
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Record Number:CaltechAUTHORS:20160520-133813535
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Usage Policy:No commercial reproduction, distribution, display or performance rights in this work are provided.
ID Code:67214
Deposited By: George Porter
Deposited On:20 May 2016 20:45
Last Modified:26 Nov 2019 11:15

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