Ligand Binding to Telomeric DNA G-quadruplex through Metadynamics Calculations

Telomeres are DNA-proteins complexes which protect the ends of human chromosomes. Telomeric DNA consists of repetitive Guanine-rich (G-rich) sequences which can fold into unusual structural motifs termed G-quadruplexes (G4). In recent times, DNA G4 have emerged as promising targets in anticancer therapy since G4 ligands are able to promote apoptosis in tumor cells. Most of G4 binders are end-stackers whose clinical use is hampered by poor drug-like properties and weak selectivity. Such properties are instead improved in G4 groove binders. Among these, 3-benzothiazol-2-yl-7-hydroxy-8-{[4-(2-hydroxyethyl)piperazinyl]methyl}chrom-en-2-one has been identified as a potent groove binder of the G4 [d(TGGGGT)]4. Here we have set up a metadynamics-based protocol to disclose at molecular level the binding mechanism of this compound to the G4 [d(TGGGGT)]4. Our approach has allowed dealing with target flexibility and solvation during ligand binding and computing the binding free energy of the ligand/DNA G4 complex. Finally, once the binding free energy surface was converged, the lowest energy binding modes have been identified. Our computational protocol is of valuable help for future studies on ligand/DNA interaction and the development of new potent and selective DNA binders.