Configurational entropy change of netropsin and distamycin upon DNA minor-groove binding

¹ Faculty of Chemistry and Chemical Technology, University of Ljubljana, Slovenia
² Laboratory of Physical Chemistry, Swiss Federal Institute of Technology, ETH-Honggerberg, Zurich
³ Dept. of Pharamcochemistry, Vrije Universiteit Amsterdam

^* To whom correspondence should be addressed. E-mail: wfvgn{at}igc.phys.chem.ethz.ch.

Submitted on September 19, 2005
Revised on October 24, 2005
Accepted on 31 March 2006

	Abstract

Binding of a small molecule to a macromolecular target reduces its conformational freedom resulting in a negative entropy change which 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 entropies 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 loose 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.

Key Words: DNA force field, GROMOS, conformational sampling, covariance matrix, ligand flexibility, molecular dynamics

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