Abstract
Recent NMR study has shown that the Mg2+-coordinated Mithramycin(MTR) dimer is a DNA-binding antitumor agent bound to a widened minor groove. Centering about the sequence-specific (G-C)·(G-C) binding site leads to the significant curvature of the helix conformation which facilitates binding of the dimer drug, such as the kink at the inter-mediate TpA step. Thus its minor groove is widened from B- to A-type. For this DNA model, d(TAGCTAGCTA)2, which contains two partially overlapping potential binding sites(GpC), recent spectroscopic study shows that the different binding stoichiometry (ligand:receptor =2:1, 1:1) for Mithramycin and Chromomycin A3 (both of which belong to the aureolic acid group and are with similar structure). This results from the different conformational flexibility due to the nature of substituents in the saccharides of the both. Here, a molecular dynamics simulation study along with the analysis of free energy on different stoichiometry of MTR2-DNA* is presented and compared with the experiment results described above. The binding free energy estimated in this study is -5.26 Kcal 1/mol which is in good greement with the experiment result,-5.4 Kcal 1/mol.The associations are presumably enthalpy-driven for two binding model(ligand:receptor = 2:1, 1:1), and on the basis of enthalpy considerations alone(including a salvation correction), the interaction of MTR with this DNA is somewhat cooperative. The interaction between each part of MTR and DNA* is further discussed in this study.