Role of mg2+ in chromomycin a3 - DNA interaction: a molecular modeling study

Chromomycin A(3) (CHR) is an antitumor antibiotic that inhibits macromolecular biosynthesis by reversibly binding to double stranded DNA via the minor groove, with GC-base specificity. At and above physiological pH when CHR is anionic, interaction of CHR with DNA requires the presence of divalent metal ions like Mg(2+). However, at acidic pHthe molecule is neutral and it binds DNA even in absence of Mg(2+). Molecular dynamics simulation studies at 300K of neutral CHR and 1:1 CHR:Mg(2+) complexes formed at pH 5.2 and 8.0 show that hydrophobicity of CHR:Mg(2+) complex formed with the neutral drug is greater than that of the two other species. Interactions of CHR with DNA in presence and absence of Mg(2+) have been studied by simulated annealing to understand the role of Mg(2+) in the DNA binding potential of CHR. This shows that the antibiotic has the structural potential to bind to DNA even in the absence of metal ion. Evaluation of the direct interaction energy between the ligand and DNA does not explain the observed GC-base specificity of the antibiotic. When energy contributions from structural alteration of the interacting ligand and DNA as a sequel to complex formation are taken into account, atrue picture of the theoretical binding propensity emerges. This implies that DNA and/or the ligand undergo significant structural alterations during the process of association, particularly in presence of Mg(2+). Accessible surface area calculations give idea about the entropy contribution to the binding free energy which is found to be different depending upon the presence and absence of Mg(2+).