An ab initio quantum mechanics calculation that correlates with ligand orientation and DNA cleavage site selectivity in camptothecin-DNA-topoisomerase I ternary cleavage complexes.

Camptothecin (CPT), a cytotoxic natural alkaloid isolated from Camptotheca acuminata, and its derivatives represent an important class of cancer chemotherapeutic drugs that act by inhibiting topoisomerase I (top1). The mechanism of top1 inhibition by CPT has been determined by X-ray crystallography. Biochemical studies carried out both in vitro and in vivo indicated that CPT has strict DNA sequence preference for -1 T and strong preference for +1 G at the cleavage site. To understand the molecular determinants for the CPT binding orientation and DNA sequence selectivity, we present a quantum mechanics calculation where only pi-pi stacking interactions were included to shed some light on the mechanism of this sequence selectivity. This ab initio calculation can not only reproduce the experimental binding orientation of CPT at the cleavage site but also shows very good correlation between the binding energy for different sequences and the observed frequency of CPT-stabilized sites in the SV40 viral genome. Therefore, it can be concluded that hydrogen bonding of the ligand to the surrounding amino acid residues of the protein is of minor significance. The present method should be applicable to other polycyclic top1 inhibitors.