Kinetics and structural aspects of the cisplatin interactions with guanine: A quantum mechanical description

The interaction of cisplatin with guanine DNA bases has been investigated using ab initio Hartree-Fock (HF) and density functional levels of theory in gas phase and aqueous solution. The overall process was divided into three steps: the reaction of the monoaqua [Pt(NH3)(2)Cl(H2O)](+) species with guanine (G) (reaction 1), the hydrolysis process yielding the adduct [Pt(NH3)(2)(G) (H2O)](2+) (reaction 2) and the reaction with a second guanine leading to the product [Pt(NH3)(2)(G)(2)](2+) (reaction 3). The functionals B3LYP, BHandH, and mPW1PW91 were used in the present study, to develop an understanding of the role of the distinct models. The geometries presented for the intermediate structures were obtained by IRC calculations from the transition state structure for each reaction. The structural analysis for the intermediates and transition states showed that hydrogen bonds with the guanine O6 atom play an important role in stabilizing these species. The geometries were not very sensitive to the level of theory applied with the HF level, giving a satisfactory overall performance. However, the energy barriers and the rate constants were found to be strongly dependent on the level of calculation and basis set, with the DFT calculations giving more accurate results. For reaction 1 the rate constant calculated in aqueous solution at PCM-BH and H/6-311G* (k(1) = 7.55 X 10(-1) M-1 s(-1)) was in good agreement with the experiment (5.4 X 10(-1) M-1 s(-1)). The BH and H/6-31G* calculated gas phase rate constants for reactions 2 and 3 were: k(2) = 0.9 X 10(-6) M-1 s(-1) and k(3) = 2.99 X 10(-4) M-1 s(-1) in fairly good accordance with the experimental findings for reaction 2 (1.0 X 10(-6) M-1 s(-1)) and reaction 3 (3.0 X 10(-4) M-1 s(-1)). (C) 2006 Wiley Periodicals, Inc.