Relative binding affinities of distamycin and its analog to d(CGCAAGTTGGC).d(GCCAACTTGCG): comparison of simulation results with experiment.
Relative binding affinities of distamycin and its analog to d(CGCAAGTTGGC).d(GCCAACTTGCG): comparison of simulation results with experiment.
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偏端霉素及其类似物与 d(CGCAAGTTGGC).d(GCCAACTTGCG) 的相对结合亲和力：模拟结果与实验结果的比较。
DOI：
10.1073/pnas.91.16.7673
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发表时间：
1994
影响因子：
11.1
通讯作者：
Kollman,PA
中科院分区：
文献类型：
--
作者：
Singh,SB;Wemmer,DE;Kollman,PA
我们在这里报告的努力，使用分子动力学/自由能微扰方法来计算两个相关的药物与DNA的相对结合亲和力。具体来说，我们专注于偏端霉素（Dst）和它的类似物，2-咪唑偏端霉素（2-ImD），以d（CGCAAGTTGGC）.d（GCCAACTTGCG）的相对结合自由能。吡咯（Dst）和咪唑变体（2-ImD）的不同之处仅在于C-H在中心环中被N取代。这些计算的起始构象是先前确定的上述11个残基DNA的小沟中的两个2-ImD分子的溶液结构。在该配合物中，两个配体的咪唑氮（N3）都朝向G6的氨基。然而，仅配体1（位点I）具有在G6的N2氨基质子的氢键距离内的N3。我们已经计算了2-ImD与Dst在三种不同情况下的结合自由能的差异，通过可逆地突变2-ImD->Dst。在第一种情况下，配体1（位点I）突变，在第二种情况下，配体2（位点II）突变，在第三种情况下，两种配体都突变。这些计算表明，在位点I处，Dst的结合亲和力比2-ImD弱0.7 kcal/mol，在位点II处，Dst的结合亲和力比2-ImD强2.9 kcal/mol，并且当占据位点I和位点II时，Dst的结合亲和力比2-ImD大1.8 kcal/mol。最近的实验结果同意半定量（1千卡/摩尔）与这里提出的计算。因此，这里提出的方法可以用来预测两个或两个以上密切相关的分子与DNA的相对结合能。
We report here an effort to use molecular dynamics/free energy perturbation methodology to calculate relative binding affinities of two related drugs to DNA. Specifically, we focus on the relative binding free energies of distamycin (Dst) and its analog, 2-imidazoledistamycin (2-ImD), to d(CGCAAGTTGGC).d(GCCAACTTGCG). The pyrrole (Dst) and the imidazole variant (2-ImD) differ only in that the C-H is substituted by an N in the central ring. The starting conformation for these calculations was the previously determined solution structure of two 2-ImD molecules in the minor groove of the above 11-residue DNA. In this complex both the ligands have the imidazole nitrogen (N3) oriented toward the amino group of G6. However only ligand 1 (site I) has N3 within the hydrogen bonding distance from N2 amino proton of G6. We have calculated the difference in free energy of binding of 2-ImD versus Dst in three different cases by mutating 2-ImD-->Dst reversibly. In the first case ligand 1 (site I) is mutated, in the second case ligand 2 (site II) is mutated, and in the third case both the ligands are mutated. These calculations show that at site I Dst has weaker binding affinity than 2-ImD by 0.7 kcal/mol, at site II Dst has stronger binding affinity than 2-ImD by 2.9 kcal/mol, and when occupying both site I and site II, Dst binds with greater affinity than 2-ImD by 1.8 kcal/mol. Recent experimental findings agree semiquantitatively (within 1 kcal/mol) with the calculations presented here. Hence the methodology presented here can be used to predict relative binding energies of two or more closely related molecules to DNA.