| Abstract
| - The first and second substitution reactions between activated (hydrolyzed) cisplatin, Pt(NH3)2(H2O)22+, andpurine bases guanine and adenine are explored using the B3LYP hybrid functional, IEF−PCM solvationmodels, and large basis sets. The computed free energy barrier for the first substitution is 19.5 kcal/mol forguanine (exptl value = 18.3 kcal/mol) and 24.0 kcal/mol for adenine. The observed predominance towardguanine in the first substitution is explained in terms of significantly larger stabilization energy for the initiallyformed complex, compared with adenine, in combination with favored kinetics, and represents a revisedview of the proposed mechanism for cisplatin binding to DNA. For the second substitution, the computedbarrier for Pt(NH3)2G22+ head-to-head formation is 22.5 kcal/mol, in very good agreement with experimentaldata for adduct closure (23.4 kcal/mol). Again, a higher stability in complexation with G over A is ascribedas the main contributing factor favoring G over A substitution. The calculations provide a first explanationfor the predominance of 1,2-d(GpG) over 1,2-d(ApG) intrastrand didentate adducts, and the origin of the5‘−3‘ direction specificity of the 1,2-d(ApG) adducts.
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