A molecular dynamics study of the bis-intercalation complexes of echinomycin with d(ACGT)2 and d(TCGA)2: rationale for sequence-specific Hoogsteen base pairing.

The behavior of the complexes of echinomycin with the DNA tetramers d(ACGT)2 and d(TCGA)2, in which the terminal AT base pairs are in either a Hoogsteen or a Watson-Crick conformation, has been explored by molecular dynamics taking into account experimental data from NMR studies (Gao and Patel. Biochemistry 1988, 27, 1744-1751). The DNA binding specificity of echinomycin appears to be the result of a subtle balance between stabilizing and destabilizing forces. Among the former is a number of hydrogen bonds between the alanine residues of echinomycin and both the N3 and 2-amino groups of the guanine bases which decisively determine the strong affinity of the antibiotic for CpG steps. On the other hand, there appears to be an unfavorable dipolar interaction between the chromophores of the antibiotic and the CpG step. This electrostatic component of the stacking interactions also contributes to explaining the conformational preferences of the flanking sequences: upon Hoogsteen pairing, the dipole moment of an AT base pair is found to increase significantly and alter its relative orientation. In the d(ACGT)2:echinomycin complex, this arrangement helps to improve the stacking interactions with the quinoxaline-2-carboxamide system, but would lead to unfavorable dipolar interactions in the d(TCGA)2 complex. The bearing of these findings on the binding of echinomycin to several sequences as well as on the altered binding selectivity of other members of the quinoxaline family of antibiotics is also discussed.