Topoisomerase I (top1) is the sole chemotherapeutic target for the anticancer alkaloid camptothecin and its analogs (CPTs). The CPTs mediate cytotoxicity by binding reversibly to transient top1-DNA covalent complexes. There is significant variation in the persistence of the resultant CPTs-top1-DNA ternary complexes formed. Presently, there is no reliable method that can be used to predict the persistence of the ternary complexes, significantly limiting formulation of structure-activity relationships. Here, we used molecular dynamics simulations to probe the properties of several CPTs that form ternary complexes of greatly variable persistence. Our study reveals that correlated motions primarily occur between the CPTs and the flanking base pairs. We envision that the nature and strength of the interactions between the CPTs and the flanking base pairs are of key importance and can shed light on the mechanistic basis for the differing persistence of the ternary complexes. Our 'flanking base pairs' models further reveal that the most persistent CPTs (i) have higher calculated free-energy barriers for drug dissociation from the flanking base pairs, (ii) are less sensitive to changes in the rotation angles of the flanking base pairs, (iii) form stronger van der Waals and hydrophobic interactions, and (iv) have larger stacking areas with the flanking base pairs. Collectively, our study demonstrates that molecular dynamics simulations can be used to gain mechanistic insight into the molecular basis for the persistence of the ternary complexes and predict the persistence of such complexes during the drug discovery process.