A Molecular Mechanics AMBER-Type Force Field for Modeling Platinum Complexes of Guanine Derivatives

Abstract

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/aine 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)12+ (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 06-HN(amine/aine) H-bonding. An empirical charge distribution method was used to modify the atomic point charges on the cis-[PtA2Gz] moiety, where A = amine or l/2 of a diamine. In general, widely used procedures were adopted. For example, a distance-dependent dielectric constant of E = 4ru 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-totail 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-[PtA2G2] species.