Raber Johan, Zhu Chuanbao, Eriksson Leif A
Department of Cell and Molecular Biology, Uppsala University, Box 596, 751 24 Uppsala, Sweden.
J Phys Chem B. 2005 Jun 2;109(21):11006-15. doi: 10.1021/jp050057d.
The first and second substitution reactions between activated (hydrolyzed) cisplatin, Pt(NH3)2(H2O)2(2+), and purine bases guanine and adenine are explored using the B3LYP hybrid functional, IEF-PCM solvation models, and large basis sets. The computed free energy barrier for the first substitution is 19.5 kcal/mol for guanine (exptl value = 18.3 kcal/mol) and 24.0 kcal/mol for adenine. The observed predominance toward guanine in the first substitution is explained in terms of significantly larger stabilization energy for the initially formed complex, compared with adenine, in combination with favored kinetics, and represents a revised view of the proposed mechanism for cisplatin binding to DNA. For the second substitution, the computed barrier for Pt(NH3)2G2(2+) head-to-head formation is 22.5 kcal/mol, in very good agreement with experimental data for adduct closure (23.4 kcal/mol). Again, a higher stability in complexation with G over A is ascribed as the main contributing factor favoring G over A substitution. The calculations provide a first explanation for the predominance of 1,2-d(GpG) over 1,2-d(ApG) intrastrand didentate adducts, and the origin of the 5'-3' direction specificity of the 1,2-d(ApG) adducts.
使用B3LYP杂化泛函、IEF-PCM溶剂化模型和大基组，研究了活化（水解）顺铂Pt(NH3)2(H2O)2(2+)与嘌呤碱鸟嘌呤和腺嘌呤之间的一级和二级取代反应。计算得出鸟嘌呤一级取代的自由能垒为19.5千卡/摩尔（实验值 = 18.3千卡/摩尔），腺嘌呤为24.0千卡/摩尔。一级取代中观察到的对鸟嘌呤的优先性，是由于与腺嘌呤相比，初始形成的配合物具有显著更大的稳定能，再加上有利的动力学，这代表了对顺铂与DNA结合机制的修正观点。对于二级取代，计算得出Pt(NH3)2G2(2+)头对头形成的能垒为22.5千卡/摩尔，与加合物闭合的实验数据（23.4千卡/摩尔）非常吻合。同样，与腺嘌呤相比，与鸟嘌呤络合时更高的稳定性被认为是有利于鸟嘌呤取代腺嘌呤的主要因素。这些计算首次解释了链内双齿加合物中1,2-d(GpG)比1,2-d(ApG)占优势的原因，以及1,2-d(ApG)加合物5'-3'方向特异性的起源。
