Nanosecond molecular dynamics simulations of parallel and antiparallel guanine quadruplex DNA molecules

Molecular dynamics (MD) simulations are presented of four-stranded G-DNA mo lecules formed by the sequences d(G(4)) and d(G(4)T(4)G(4)) Starting coordi nates are based on high-resolution X-ray structures or NMR data. Simulation s of the all-parallel d(G(4)) quadruplex with sodium cations in the central ion channel yield exceptionally stable trajectories on the nanosecond scal e. Simulations without cations in the channel show destabilization of the G -DNA structure, underscoring the central role of these ions for the structu ral integrity of the molecule. Further simulations reveal that the cation-s tabilized d(G)(4) stem can adopt an alternative very stable conformation in volving a guanine base triad. Simulations of d(G(4)T(4)G(4)) quadruplexes i ndicate a similar rigidity and stability of the antiparallel guanine stem a s for the parallel d(G(4)) conformer. The simulations further demonstrate s ignificant geometrical plasticity of the thymine residues arranged in four- nucleotide loops, including loop geometries capable of coordinating to a so dium cation from the ion channel via thymine carbonyl groups. All simulatio ns were carried out with the AMBER4.1 force field, using the particle mesh Ewald (PME) technique for electrostatic interactions, with the total length of all simulations reaching 25 ns. The calculations indicate some inaccura cies of the force field description for a direct interaction between cation s and guanine quartets likely due to the pair-additive nature of the force field. Moderate perturbation of the hydrogen bonding geometries in quartet layers is noted, giving rise to bifurcated hydrogen bonds. However, the ove rall results of the simulations show an excellent performance of the PME MD technique and AMBER4.1 force field for these unusual nucleic acids.