COMPUTER-SIMULATION OF THE BINDING OF SAFRAMYCIN-A TO D(GATGCATC)2

The binding of Saframycin A to the octanucleotide duplex d(GATGCATC)2 was investigated using molecular dynamics. For covalent binding at N2 of the central guanine, only the R configuration at the alkylating carbon (C7) was permitted for B DNA and the 3' direction in the minor groove was preferred by 50.6 kcal/mol. The dihydroquinone form of saframycin A gave stronger binding than the quinone, in agreement with the literature. Addition of solvent and counterions made no significant change in the geometry model. The proposed mechanism of DNA alkylation, involving iminium ion intermediates from the dihydroquinone or quinone, was investigated by modeling these species. They gave models with good net binding enthalpies, and C7 was in close proximity to N2 of guanine. The noncovalent binding of saframycin A and its dihydroquinone in the vicinity of guanine also was favorable in the 3' direction.