Dynamics simulation of the interaction between the novel intercalator diethidium cation and B-form DNA

Previous research has described the interaction between the novel molecule diethidium (2,7-diamino 9-[2,7 diamino 10-N-phenanthridium] 10-N-phenanthridium) (Figure 1) and B-form DNA. Our goal is the elucidation of diethidium as the first member of a novel class of drugs which are potential pharmaceutical agents. This class of potential drug molecules differs from previously known intercalators in the following ways: a) Its structure, that of two perpendicular planes, each known to have excellent intercalation properties, is novel b) Unlike known bis-intercalators, the linker region length in diethidium is zero c) The geometry of the drug matches the geometry of the space available in the major groove d) The drug is shown to cause some vectorial disruption of DNA. For this paper, we have performed a series of 200 picosecond dynamics simulations on the complex formed between diethidium in the major groove and a dodecarner of double-stranded B-form DNA, CGCGAATTCGCG, and have shown that this complex has a intricate interaction. The 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 mobile within the intercalation site on timescales longer than 1 nanoscale. The mobility of the drug within the intercalation site has been predicted by our previous energy minimization studies.