DYNAMICS SIMULATION OF THE INTERACTION BETWEEN THE NOVEL INTERCALATORDIETHIDIUM CATION AND B-FORM DNA

Previous research(1) has described the interaction between the novel m olecule diethidium (2,7-diamino 9-[2,7 diamino 10-N-phenanthridium] 10 -N-phenanthridium) (Figure I) and B-form DNA. Our goal is the elucidat ion of diethidium as the first member of a novel class of drugs which are potential pharmaceutical agents. This class of potential drug mole cules differs from previously known intercalators in the following way s: a) Its structure, that of two perpendicular planes, each known to h ave excellent, intercalation properties, is novel b) Unlike known bis- intercalators, the linker region length in diethidium is zero c) The g eometry of the drug matches the geometry of the space available in the major groove. d) The drug is shown(1) to cause some vectorial disrupt ion of DNA. For this paper, we have performed a series of 200 picoseco nd dynamics simulations on the complex formed between diethidium in th e major groove and a dodecamer of double-stranded B-form DNA, CGCGAATT CGCG, and have shown that this complex has a intricate interaction. Th e DNA dodecamer is found to be in an intermediate A-B state, but, even in simulations as long as 1 nanosecond, the drug does not back-out or otherwise leave the intercalation site. The drug is found to be mobil e within the intercalation site on timescales longer than 1 nanoscale. The mobility of the drug within the intercalation site has been predi cted by our previous energy minimization studies.