Molecular mechanics calculations and molecular dynamics simulations have been used to study the binding of the partially inserted major groove complex of A-[Ru(l, 10-phenanthroline)3]2+ with DNA. Energy refinements of this complex showed a clear preference for binding at purine-3ˊ, 5ˊ-pyrimidine sites over pyrimidine-3ˊ, 5ˊ-purine sites. The basis for this difference is shown to be a slight change in the binding orientation induced by interchanging the purine and pyrimidine bases. This in turn provides for a better secondary interaction with the helix backbone at a point beyond the immediate binding site. It is this secondary interaction that provides the additional energetic stabilisation for complexes formed at purine-3ˊ, 5ˊ-pyrimidine sites. Molecular dynamics simulations including explicit representation of solvent support these conclusions and provide an insight into the positional stability of the ligand at a particular site. Repuckering of specific deoxyribose rings to the C3ˊ-endo conformation seems to be an important feature of the DNA/ligand complex.