BACKGROUND: Duplex DNA is more than a simple information carrier. The sequence-dependent structure and its inherent deformability, in concert with the subtle modulating effects of the environment, play a crucial role in the regulation and packaging of DNA. Recent advances in force field and simulation methodologies allow molecular dynamics simulations to now represent the specific effects of the environment. An understanding of the environmental dependence of DNA structure gives insight into how histones are able to package DNA, how various proteins are able to bind and modulate nucleic acid structure and will ultimately aid the design of molecules to package DNA for more effective gene therapy. RESULTS: Molecular dynamics simulations of d[ACCCGCGGGT]2 in solution in the presence of hexaamminecobalt(III) [Co(NH3)6(3+)] show stabilization of A-DNA and spontaneous B-DNA to A-DNA transitions, which is consistent with experimental results from NMR and Raman spectroscopic and X-ray crystallographic studies. In the absence of Co(NH3)6(3+), A-DNA to B-DNA transitions are observed instead. In addition to their interaction with the guanines in the major groove, Co(NH3)6(3+) ions bridge opposing strands in the bend across the major groove, probably stabilizing A-DNA. CONCLUSIONS: The simulation methods and force fields have advanced to a sufficient level that some representation of the environment can be seen in nanosecond length molecular dynamics simulations. These simulations suggest that, in addition to the general explanation of A-DNA stabilization by dehydration, hydration and ion association in the major groove stabilize A-DNA.

Cobalt(III) hexaamine ion [Co(NH3)6]3+ is known to facilitate the transition of B- to Z-DNA or B- to A-DNA depending on the DNA sequences. Specific interactions are found between the amines of [Co(NH3)6]3+ and DNA atoms of A-DNA or Z-DNA. Bridged Co(III)pentaamine complexes, with multiple amine groups arranged in a rigid framework, may enhance the effectiveness of the conformational transition by occupying simultaneously two of the Co(III) hexaamine binding sites. Therefore, the imidazole-bridged Co(III)pentaamine complexes have been synthesized and their interactions with DNA oligonucleotides investigated by circular dichroism (CD) and NMR spectroscopy. CD studies of the titrations of d(A2C15G15T2) with [(NH3)5Co(Im)Co(NH3)5]Br5 and [(NH3)5Co(Im)2Co(NH3)4]Br7 showed that the former metal compound indeed is more effective than [Co(NH3)6]3+ in inducing the transition from B- to A-DNA. The conversion of B- to A-DNA was also supported by one- and two-dimensional NMR studies. Similarly for the titrations of poly(dC-dG). poly(dC-dG) and d(m5C-G)15 with these two bridged Co(III) complexes, efficient induction of Z-DNA was observed. Our studies suggest that bridged Co(III)pentaamine complexes may be useful agents for studying nucleic acid structures.