INSIGHT INTO THE STABILIZATION OF A-DNA BY SPECIFIC ION ASSOCIATION -SPONTANEOUS B-DNA TO A-DNA TRANSITIONS OBSERVED IN MOLECULAR-DYNAMICSSIMULATIONS OF D[ACCCGCGGGT](2) IN THE PRESENCE OF HEXAAMMINECOBALT(III)

Background: Duplex DNA is more than a simple information carrier. The sequence-dependent structure and its inherent deformability, in concer t with the subtle modulating effects of the environment, play a crucia l role in the regulation and packaging of DNA. Recent advances in forc e field and simulation methodologies allow molecular dynamics simulati ons to now represent the specific effects of the environment. An under standing of the environmental dependence of DNA structure gives insigh t into how histones are able to package DNA, how various proteins are able to bind and modulate nucleic acid structure and will ultimately a id the design of molecules to package DNA for more effective gene ther apy. Results: Molecular dynamics simulations of d[ACCCGCGGGT](2) in so lution in the presence of hexaamminecobalt(III) [Co(NH3)(6)(3+)] show stabilization of A-DNA and spontaneous B-DNA to A-DNA transitions, whi ch is consistent with experimental results from NMR and Raman spectros copic 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, pr obably stabilizing A-DNA. Conclusions: The simulation methods and forc e 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 gener al explanation of A-DNA stabilization by dehydration, hydration and io n association in the major groove stabilize A-DNA.