Dynamics Simulation of the Interaction Between the Novel Intercalator Diethidium Cation and B-Form DNA

Abstract

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.

Complex of B-DNA with Polyamides Freezes DNA Backbone Flexibility

“…[14][15][16] These ligands and other recently designed molecules with the potential to control transcription [17][18][19] are of great interest as antitumor, antiviral and antimicrobial agents. [20][21][22][23][24][25][26][27][28][29][30][31][32][33] Often a dimeric com-plexation of these ligands is observed. [34][35][36] In the case of the polyamides studied here, such a dimer binds in an antiparallel arrangement, by building specific contacts with the DNA.…”

B-DNA's BI → BII Conformer Substate Dynamics Is Coupled with Water Migration

“…The sequence investigated here, d(CGCGAATTCGCG) 2 , is also known as the “ Eco RI dodecamer” because its central six base pairs are the recognition site for the Eco RI endonuclease. This dodecamer duplex was the first oligonucleotide duplex found to be in the B-form of DNA ,− and subsequently was the target of further crystallographic experiments. , Additionally, a large number of both experimental and theoretical studies including NMR experiments, − Raman spectroscopic investigations, and MD simulations ,,− was carried out and excellently reviewed by Young et al In the crystalline form, the Eco RI dodecamer displays unsymmetric axis bending at the junctions between AATT and CGCG which, taking into account the symmetry of the sequence, was interpreted to result from crystal packing effects 40,41 and/or the kinetics of crystallization .…”

“…This dodecamer duplex was the first oligonucleotide duplex found to be in the B-form of DNA 23,[39][40][41][42][43][44][45] and subsequently was the target of further crystallographic experiments. 46,47 Additionally, a large number of both experimental and theoretical studies including NMR experiments, [48][49][50] Raman spectroscopic investigations, 51 and MD simulations 31,49,[52][53][54][55][56][57][58][59][60][61] was carried out and excellently reviewed by Young et al 31 In the crystalline form, the EcoRI dodecamer displays unsymmetric axis bending at the junctions between AATT and CGCG which, taking into account the symmetry of the sequence, was interpreted to result from crystal packing effects 40,41 and/or the kinetics of crystallization. 23 These suggestions are confirmed by the fact that the slightly modified CGCGAATT Br CGCG dodecamer under different conditions crystallizes in a straight conformation.…”

Helix Morphology Changes in B-DNA Induced By Spontaneous BI⇌BIISubstate Interconversion

“…The well examined d(CGCGAATICGCGh model sequence (X-ray crystallography (46)(47)(48)(49)(50)(51)(52)(53)(54)(55)(56), NMR experiments (57-61), Raman spectroscopic investigations (62) and MD simulations (35,36,43,44,58,(63)(64)(65)(66)(67)(68)), also known as the "EcoRI dodecamer", was used to investigate B-form substate dynamics.…”