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Configurational Entropy Change of Netropsin and Distamycin upon DNA Minor-Groove Binding

Joica Dolenc ^* , Riccardo Baron , Chris Oostenbrink , Joe Koller ^* and Wilfred F. van Gunsteren 

^* Faculty of Chemistry and Chemical Technology, University of Ljubljana, Ljubljana, Slovenia; Laboratory of Physical Chemistry, Swiss Federal Institute of Technology, Zurich, Switzerland; and Computational Medicinal Chemistry and Toxicology, Department of Pharmacochemistry, Vrije Universiteit, Amsterdam, The Netherlands

Correspondence: Address reprint requests to Wilfred F. van Gunsteren, Laboratory of Physical Chemistry, Swiss Federal Institute of Technology, ETH-Hönggerberg, CH-8093, Zurich, Switzerland. Tel.: 41-1-6325501; Fax: 41-1-6321039; E-mail: wfvgn{at}igc.phys.chem.ethz.ch.

Binding of a small molecule to a macromolecular target reduces its conformational freedom, resulting in a negative entropy change that opposes the binding. The goal of this study is to estimate the configurational entropy change of two minor-groove-binding ligands, netropsin and distamycin, upon binding to the DNA duplex d(CGCGAAAAACGCG)·d(CGCGTTTTTCGCG). Configurational entropy upper bounds based on 10-ns molecular dynamics simulations of netropsin and distamycin in solution and in complex with DNA in solution were estimated using the covariance matrix of atom-positional fluctuations. The results suggest that netropsin and distamycin lose a significant amount of configurational entropy upon binding to the DNA minor groove. The estimated changes in configurational entropy for netropsin and distamycin are –127 J K^–1 mol^–1 and –104 J K^–1 mol^–1, respectively. Estimates of the configurational entropy contributions of parts of the ligands are presented, showing that the loss of configurational entropy is comparatively more pronounced for the flexible tails than for the relatively rigid central body.

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