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 mole cular dynamics taking into account experimental data from NMR studies (Gao and Patel. Biochemistry 1988,27,1744-1751). The DNA binding speci ficity of echinomycin appears to be the result of a subtle balance bet ween stabilizing and destabilizing forces. Among the former is a numbe r of hydrogen bonds between the alanine residues of echinomycin and bo th the N3 and 2-amino groups of the guanine bases which decisively det ermine the strong affinity of the antibiotic for CpG steps. On the oth er hand, there appears to be an unfavorable dipolar interaction betwee n the chromophores of the antibiotic and the CpG step. This electrosta tic component of the stacking interactions also contributes to explain ing the conformational preferences of the flanking sequences: upon Hoo gsteen pairing, the dipole moment of an AT base pair is found to incre ase significantly and alter its relative orientation. In the d(ACGT)2: echinomycin complex, this arrangement helps to improve the stacking in teractions with the quinoxaline-2-carboxamide system, but would lead t o unfavorable dipolar interactions in the d(TCGA)2 complex. The bearin g 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.