title: Molecular mechanism of direct proflavine-DNA intercalation: evidence for drug-induced minimum base-stacking penalty pathway.
abstract: DNA intercalation, a biophysical process of enormous clinical significance, has surprisingly eluded molecular understanding for several decades. With appropriate configurational restraint (to prevent dissociation) in all-atom metadynamics simulations, we capture the free energy surface of direct intercalation from minor groove-bound state for the first time using an anticancer agent proflavine. Mechanism along the minimum free energy path reveals that intercalation happens through a minimum base stacking penalty pathway where nonstacking parameters (Twist→Slide/Shift) change first, followed by base stacking parameters (Buckle/Roll→Rise). This mechanism defies the natural fluctuation hypothesis and provides molecular evidence for the drug-induced cavity formation hypothesis. The thermodynamic origin of the barrier is found to be a combination of entropy and desolvation energy.
authors.affiliation: Chemistry Department, Indian Institute of Science Education and Research, Pune-411021, India.
authors.forename: Wilbee D
authors.initials: WD
authors.lastname: Sasikala
authors.forename: Arnab
authors.initials: A
authors.lastname: Mukherjee
mesh_terms: D000970:Antineoplastic Agents / Q000737:chemistry* / Q000494:pharmacology; D004247:DNA / Q000737:chemistry* / Q000187:drug effects; D008958:Models, Molecular; D056004:Molecular Dynamics Simulation; D011370:Proflavine / Q000737:chemistry* / Q000494:pharmacology; D013816:Thermodynamics
chemical_list: D000970:Antineoplastic Agents; D004247:DNA; D011370:Proflavine