Binding of Echinomycin to d(GCGC)₂and 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, 93-138 (1989)]. The conformational preferences appear to arise mainly from differential stacking interactions in which the electrostatic component is shown to play a dominant role. Differences in hydrogen bonding patterns are also found among the complexes and these are compared in relation to available crystal structures. The binding of echinomycin to DNA appears as a complex process involving many interrelated variables.

Modulation of Hoogsteen dynamics on DNA recognition

“…The narrowed and more negatively charged minor groove flanking the two A–T Hoogsteen bps has been proposed to form favorable electrostatic interactions with a positively charged arginine residue 9 . Hoogsteen bps have also been observed in DNA–small molecule complexes 15 – 17 , which are proposed to be stabilized by stacking interactions 18 , 19 .…”

Molecular Dynamics Simulations of the Bis-Intercalated Complexes of Ditercalinium and Flexi-Di with the Hexanucleotide d(GCGCGC)2: Theoretical Analysis of the Interaction and Rationale for the Sequence Binding Specificity

“…In the natural antibiotics triostin A or echinomycin, the two chromophores are attached to a depsipeptide, which establishes a number of hydrogen bonds with the DNA minor groove. These hydrogen bonds are effectively shielded from competitive interactions with the water molecules 25,26 in a manner similar to what is observed in actinomycin D-DNA complexes. 58 For ditercalinium and Flexi-Di, this is clearly not the case, and the linkers of these molecules can be expected to contribute to the overall binding affinity but not to the sequence specificity.…”

“…This procedure was repeated as needed until electroneutrality was achieved for each system, and each sodium ion replaced a water molecule from the equilibrated box of solvent. This novel method favored equilibration of the systems to a larger extent than other previously reported methods 25,26 (data not shown) since the sodium ions were more effectively located in minimum energy configurations.…”

“…23 Since the orientation of the N,N′-diethyl-1,6-hexanediammonium linker of Flexi-Di increases the hydrogen bonding potential of this linker over that of the more rigid bis(ethylpiperidinium) spacer of ditercalinium, it was proposed that DNA bending originates in these complexes by a concerted push/pull effect mechanism involving specific hydrogen bonding and base pairchromophore stacking interactions. 23 We thought it would be of considerable interest to analyze these stacking interactions in detail because we have previously shown their relative importance in determining binding specificity 24 and dictating DNA conformational preferences 25,26 in other bis-intercalator-DNA complexes. We were also interested in probing, by simulation methods, to what extent the amount and the direction of bending could be influenced by lattice forces and by the presence of surrounding complexes in the crystal, which must surely give rise to a very different electrostatic environment from that of the complex in aqueous solution.…”

Stability of the I-motif Structure Is Related to the Interactions between Phosphodiester Backbones

“…The additional H3 hydrogen of protonated cytosine was of AMBER type H (i.e., an hydrogen bonded to the nitrogen atoms; Cornell et al, 1995). The partial charges of the protonated cytosine were those used by Gallego et al (1994).…”