Binding of Echinomycin to d(GCGC)2 and d(CCGG)2: Distinct Stacking Interactions Dictate the Sequence-Dependent Formation of Hoogsteen Base Pairs

Abstract Molecular dynamics simulations have been used to explore the behavior of the complexes of echinomycin with the DNA tetramers d(GCGC)2 and d(CCGG)2 in which the terminal bases have been paired according to either a Hoogsteen or a Watson-Crick hydrogen bonding scheme. The energy of the four resulting complexes has been monitored along the dynamics trajectories and the interaction energy between echinomycin and DNA has been decomposed into contributions arising from the planar aromatic systems and the depsipeptide part of the antibiotic. Our calculations predict a large increase in overall stabilization upon protonation of the terminal cytosines and subsequent Hoogsteen pair formation in the complex of echinomycin with d(GCGC)2 but not with d(CCGG)2, in agreement with the experimental evidence [Gao and Patel, Quart. Rev. Biophys. 22,93-13 8 (1989)]. The conformational preferences appear to arise mainly from differential stacking interactions in which the electrostatic component is shown to play a do...