A MOLECULAR MECHANICS AMBER-TYPE FORCE-FIELD FOR MODELING PLATINUM COMPLEXES OF GUANINE DERIVATIVES

A force field, developed and designated here as DNA/Pt, was optimized for modeling Pt ammine/amine complexes of guanine derivatives (G) bound via N7. DNA/Pt was based on the all-atom type force field of Weiner et al. (Weiner, S. J.; Kollman, P. A.; Nguyen, D. T.; Case, D. A. J. Comput. Chem. 1986, 7, 230) as modified by Veal and Wilson (Veal, J. M.; Wilson, D. W. J. Biomol. Struct. Dyn. 1991, 8, 1119). New atom types were created for Pt, N7 of G, and the amine/ammine N and H atoms. Force field parameters for these new atom types were developed by comparing force field parameters found in the literature with the structural features of published crystal structures. Pt out-of-plane bending was treated by a single improper torsion barrier, C8-N7-C5-Pt. The force constant parameter for the improper torsional deformation barrier was determined in this study by fitting the resulting out-of-plane bending potential curve onto the corresponding profile from ab initio calculations on [Pt(NH3)(3)(Ade)](2+) (Kozelka, J.; Savinelli, R.; Berthier, G.; Flament, J.-P.; Lavery, R. J. Comput. Chem. 1993, 14, 45). The DNA/Pt force field, also includes parameters for the van der Waals radius of the Pt atom and for O6-HN(amine/ammine) II-bonding. An empirical charge distribution method was used to modify the atomic point charges on the cis-[PtA(2)G(2)] moiety, where A = amine or (1)/(2) of a diamine. In general, widely used procedures were adopted. For example, a distance-dependent dielectric constant of epsilon = 4r(ij) and partially neutralized phosphates were used to represent solvent and counterion. The validity of this new DNA/Pt force field was evaluated by a number of test cases. Conformational features determined by either X-ray crystallographic or NMR techniques were reproduced well by the calculations. The rotational barriers for a number of complexes were calculated and were found to agree with NMR data quite well. The calculated relative stabilities of head-to-head and head-to-tail conformers of some complexes are also in good agreement with experimental results; Finally, an initial attempt to model lattice effects was found to improve the fit between calculated and crystal structures of the cis-[PtA(2)G(2)] species.