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) boun d 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. C omput. 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. For ce field parameters for these new atom types were developed by compari ng 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 c onstant parameter for the improper torsional deformation barrier was d etermined in this study by fitting the resulting out-of-plane bending potential curve onto the corresponding profile from ab initio calculat ions 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 ch arge distribution method was used to modify the atomic point charges o n 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 dist ance-dependent dielectric constant of epsilon = 4r(ij) and partially n eutralized phosphates were used to represent solvent and counterion. T he validity of this new DNA/Pt force field was evaluated by a number o f test cases. Conformational features determined by either X-ray cryst allographic or NMR techniques were reproduced well by the calculations . The rotational barriers for a number of complexes were calculated an d were found to agree with NMR data quite well. The calculated relativ e stabilities of head-to-head and head-to-tail conformers of some comp lexes are also in good agreement with experimental results; Finally, a n initial attempt to model lattice effects was found to improve the fi t between calculated and crystal structures of the cis-[PtA(2)G(2)] sp ecies.