Conformations of complexes between pyrrolo[1,4]benzodiazepines and DNA segments.

The molecular mechanics program AMBER, assisted by CHEMLAB II, was used to model the covalent and noncovalent binding of anthramycin, tomaymycin, and neothramycin A to the hexanucleotide conformation. Structures covalently bonded at N2 of guanine gave excellent fits when placed in either direction in the minor groove. However, energy analysis showed a preference for the direction wherein the side chain points toward the 5' end of the covalently bound strand. This preference agrees with published NMR studies. Noncovalent binding of anthramycin in the minor groove near guanine gave good fits with almost no distortion in the helix, and the reactive center of the ligand was close enough to N2 for subsequent covalent bond formation. Anthramycin also gave a good noncovalent complex near adenine in the minor groove, but binding in the major groove had decreased dispersion attractions. Binding of tomaymycin was similar to that of anthramycin, although the smaller size of tomaymycin resulted in less binding energy. Neothramycin noncovalent binding was characterized by strong electrostatic interactions, partly involving the 3-OH group, and by part of the molecule lying outside the minor groove. AMBER was used for the exploratory design of an anthramycin analogue that theoretically would bind as well as anthramycin but not cause cardiotoxicity. A related study involving anthramycin, tomaymycin, and the pentanucleotide duplex d(AAGAA/TTCTT) was undertaken to evaluate further the ability of AMBER to predict sequence specificity. It indicated a preferred direction of binding toward 5' in the minor groove of the duplex, but rather weak interaction with the noncovalently bound strand. This prediction agreed with experiments on tomaymycin that showed separation of the duplex and alignment of the drug toward the 5' end of the covalently bound strand.