Dolenc Jozica, Baron Riccardo, Oostenbrink Chris, Koller Joze, van Gunsteren Wilfred F
Faculty of Chemistry and Chemical Technology, University of Ljubljana, Ljubljana, Slovenia.
Biophys J. 2006 Aug 15;91(4):1460-70. doi: 10.1529/biophysj.105.074617. Epub 2006 May 26.
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.
小分子与大分子靶标的结合会降低其构象自由度，导致负熵变，从而不利于结合。本研究的目的是估计两种小沟结合配体——纺锤菌素和偏端霉素，与DNA双链体d(CGCGAAAAACGCG).d(CGCGTTTTTCGCG)结合时的构象熵变。基于溶液中以及与溶液中的DNA形成复合物的纺锤菌素和偏端霉素的10纳秒分子动力学模拟，利用原子位置涨落的协方差矩阵估计了构象熵上限。结果表明，纺锤菌素和偏端霉素与DNA小沟结合时会损失大量构象熵。纺锤菌素和偏端霉素的构象熵估计变化分别为-127 J K(-1) mol(-1)和-104 J K(-1) mol(-1)。给出了配体各部分构象熵贡献的估计值，表明柔性尾部构象熵的损失比相对刚性的中心体更为明显。
