MOLECULAR-DYNAMICS SIMULATION OF A PNA-CENTER-DOT-DNA-CENTER-DOT-PNA TRIPLE-HELIX IN AQUEOUS-SOLUTION

Molecular dynamics simulations have been used to explore the conformat ional flexibility of a PNA DNA PNA triple helix in aqueous solution. T hree 1.05 ns trajectories starting from different but reasonable confo rmations have been generated and analyzed in detail. All three traject ories converge within about 300 ps to produce stable and very similar conformational ensembles, which resemble the crystal structure conform ation in many details. However, in contrast to the crystal structure, there is a tendency for the direct hydrogen-bonds observed between the amide hydrogens of the Hoogsteen-binding PNA strand and the phosphate oxygens of the DNA strand to be replaced by water-mediated hydrogen b onds, which also involve pyrimidine O2 atoms. This structural transiti on does not appear to weaken the tripler structure but alters groove w idths and so may relate to the potential for recognition of such struc tures by other ligands (small molecules or proteins). Energetic analys is leads us to conclude that the reason that the hybrid PNA/DNA triple r has quite different helical characteristics from the all-DNA tripler is not because the additional flexibility imparted by the replacement of sugar-phosphate by PNA backbones allows motions to improve base-st acking but rather that base-stacking interactions are very similar in both types of tripler and the driving force comes from weak but defina te conformational preferences of the PNA strands.