BINDING OF NET-FLA, A NETROPSIN-FLAVIN HYBRID MOLECULE, TO DNA - MOLECULAR MECHANICS AND DYNAMICS STUDIES IN VACUO AND IN WATER SOLUTION

We have studied the binding of the hybrid netropsin-flavin (Net-Fla) m olecule onto four sequences containing four A. T base pairs. Molecular mechanics minimizations in vacuo, show numerous minimal conformations separated by one base pair. 400 ps molecular dynamics simulations in vacuo have been performed using the lowest minima as the starting conf ormations. During these simulations, the flavin moiety of the drug mak es two hydrogen bonds with an amino group of a neighboring guanine. A 200 ps molecular dynamics simulation in explicit water solution sugges ts that the binding of Net-Fla upon the DNA substrate is enhanced by w ater bridges. A water molecule bridging the amidinium of Net-Fla to th e N3 atom of an adenine seems to be stuck in the drug-DNA complex duri ng the whole simulation. The fluctuations of the DNA helical parameter s and of the torsion angles of the sugar-phosphate backbone are very s imilar in the simulations in vacuo and in water. The time auto-correla tion functions for the DNA helical parameters decrease rapidly in the picosecond range in vacuo. The same functions computed from the water solution molecular dynamics simulations seem to have two modes: the ra pid mode is similar to the behavior in vacuo, and is followed by a slo wer mode in the 10 ps range.