NMR and CD spectroscopy and molecular mechanics and dynamics (MMD) calculations were used to characterize (Me(2)DAP)Pr(G)(2) complexes (G = N9-substituted guanine derivative; Me(2)DAP = 2,4-bis(methylamino)pentane with N, C, C, and N stereochemistries of S,R,S,R,S,R,IZ,R, and R,R,R,R). NMR and MMD results indicated that the favored Me(2)DAP chelate ring conformations were chair. Then are two possible head-to-tail rotamers (Delta HT and Lambda HT) and, depending on the Me(2)DAP stereochemistry, one or two head-to-head (HH) rotamers. Rotation of the G bases around the Pt-N7 bond was found to be rapid on the NMR time scale for all compounds in D2O at room temperature; in contrast, slow rotation was reported for (Me(2)DAB)Pt(G)(2) (Me(2)DAB = 2,3-bis-(methylamino)butane by Xu et al.) Because of the additional flexibility of the six-membered chelate ring in the Me(2)DAP systems versus the five-membered ring in Me(2)DAB, the N-methyl groups of Me(2)DAP can occupy more pronounced axial positions, allowing a low-energy path to rotation as suggested by MMD calculations. The fast rotation necessitated that the rotamer preference be assessed by CD spectroscopy. For the S,R,S,R complexes, the G N9 substituent strongly influenced which HT rotamer was preferred, The Lambda HT rotamer was favored for the R,R,R,R complexes at pH 3 regardless of the G used. MMD calculations on the [(R,R,R,R)-(Me(2)DAP)Pt(9-EtG)(2)](2+) complex suggested amine-O6 hydrogen bonding in the Lambda HT rotamer and indicated an unfavorable nonbonded interaction between the G O6 and an axial cis C-methyl group in the Delta HT rotamer. This nonbonded interaction was also observed in calculated structures of the [(S,R,R,R)-(Me(2)DAP)Pt(9-EtG)(2)](2+) complex. for which experimental data showed a preference fur the Lambda HT rotamer as well. Thus, the orientations of the N- and C-methyl groups appear to be important in determining both the rate of rotation and the rotamer preference of the (Me(2)DAP)Pt(G)(2) systems.