Density functional and Ab initio studies on N-acetylduocarmycin SA: insight into its DNA interaction properties

Density functional (DF) and Møller-Plesset second order perturbation (MP2) calculations were carried out on N-acetylduocarmycin SA (N-Ac-DSA), an analogue of a series of potent antitumor antibiotics that include the duocarmycins. These computational methods were used to investigate the degree of ground state destabilization of duocarmycins that would result upon binding to DNA. Ground state destabilization has been proposed as the origin of the ligand's enhanced rate of alkylation by more than a millionfold. The conformations of the 'Unbound' and 'DNA-Bound' N-Ac-DSA were generated using available geometric data for duocarmycin SA. Specifically, the dihedral angles chi1/chi2 were locked at 6.9 degrees/4.5 degrees for the Unbound and 22.0 degrees/11.0 degrees for the Bound form. The structures were optimized using DF theory, with subsequent MP2 calculations to improve the electronic energies. All of the calculations were performed on the unprotonated (1) as well as the C6-carbonyl protonated form (2). The results showed that the ground state destabilization energies of the Unbound and Bound forms, for the unprotonated and protonated series, were fairly small (< 0.8 kcal/mol). Similarly, the difference in the electronic nature of the Unbound and Bound forms, as indicated by changes in bond lengths and charge density, were also small. In summary, it appears that twisting of two key torsional angles, the concomitant ground state destabilization, and C6-carbonyl protonation may not fully account for the significant rate increase of adenine-N3 alkylation upon binding to DNA.