SUNY at Albany
June 19-23, 2001
Atomic-Resolution Picture of Structure and Dynamics of G-DNA and Other Unusual DNA Molecules. Large-Scale Molecular Dynamics Simulations.
Thorough insight into the structure and dynamics of biologically important unusual DNA molecules (G-DNA, i-DNA, intercalated zipper duplex) has been obtained by state of the art molecular dynamics (MD) simulations with explicit representation of solvent and counterions and a correct treatment of long-range electrostatic interactions (1-5). The simulated structures are in excellent agreement with all available high-resolution X-ray and NMR data while the simulations provide unique additional information that can not be obtained by the experiments. Four-stranded DNA molecules are characterized by unusual mechanical and dynamical properties. The four-stranded intercalated cytosine rich i-DNA is very stable despite having repulsive base stacking interactions (1). The guanine quadruplex motif (G-DNA) is among the most interesting unusual structures that DNA can adopt. G-DNA molecules are stabilized by a string of monovalent cations presented in their ion channel. Stability of the structure is retained when reducing the number of cations in the channel while a complete removal of cations leads to large fluctuations, temporary strand slippage and marked destabilization of the molecule (2). Further simulations, however, suggest that a vacant G-DNA stem is capable to spontaneously attract a cation on a scale of 10 ns (5). We have also characterized in detail quadruplexes with mixed guanine/cytosine quartets and quadruplexes containing inosine and thioguanine (5). The inosine quadruplex with monovalent cations in the channel show the same structural and dynamical properties as guanine quadruplex but dramatic differences occur when the number of cations in the channel of inosine quadruplex is reduced (4). Vacant inosine quadruplex is irreversibly disrupted during the first nanosecond without any possibility to incorporate a cation (4). The behavior of thymine loops of many types of quadruplex structures was studied in detail (2,5). The loop geometry is suggested to be an important regulation factor of ion exchange. The simulations revealed several geometries participating in ion transport but also geometries closing the channel entrance (5). Finally, simulations of zipper duplexes revealed local conformational variations with tight phosphate clustering stabilized by sodium cations and long-residing water molecules and provided thorough insights into molecular interactions of sheared G.A mismatches (3). MD simulations of unusual nucleic acid structures represent a powerful tool for detailed studies of structure and dynamics that contribute to a better understanding of the biological, biochemical and pharmacological roles of these molecules. The total length of all our simulations exceeded 200 ps, making this one of the most extensive projects carried out to date on biopolymers.
References and Footnotes
Nada Spackova (1), Richard Stefl (2), Imre Berger (3), Jaroslav Koca (2), and Jiri Sponer (1)
(1)Lab./Nat. Centre/Biom. Res., Inst./Bioph., Acad./Sciences/Czech Republic, Kralovopolska 135, 612 65 Brno, Czech Republic (2)Lab./Nat. Centre/Biom. Res., Fac./Science, Masaryk Univ., 611 37 Brno, Czech Republic (3)Inst./Mol. Biol./Biophy., CH-8093 Zuric