THE DNA-ESPERAMICIN-A(1) COMPLEX - A MODEL-BASED ON SOLVATED MOLECULAR-DYNAMICS SIMULATIONS

A solvated model for the DNA-esperamicin complex has been constructed and shown to be thermodynamically stable over a 300-ps molecular dynamics simulation. The dynamical model is consistent with all of the available experimental data. The model has been used to gain insights into (1) how esperamicin is activated into a DNA-cleaving molecule, (2) its mode of binding to DNA, (3) how the individual esperamicin residues contribute to its ability to bind with and cleave DNA, (4) the fate of the carbon-centered radicals, and (5) its DNA-cleavage patterns and cleavage sequence specificity. Furthermore, a comparison of the models for the DNA-esperamicin A1 and DNA-esperamicin C complexes has been carried out to gain an understanding at the molecular level of the difference in the DNA-cutting abilities exhibited by these two esperamicin analogs. Finally, experimental data are presented that show that esperamicin Al undergoes fragmentation in the DNA-cleavage reaction. The DNA-esperamicin model has been used to provide a mechanistic rationale for the fragmentation reaction.