Journal
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
Volume 114, Issue 11, Pages E2136-E2145Publisher
NATL ACAD SCIENCES
DOI: 10.1073/pnas.1612627114
Keywords
funnel-metadynamics; ligand docking; ligand binding free energy; free-energy calculations; DNA G-quadruplex
Categories
Funding
- European Cooperation in Science and Tecnology (COST Action) [CA15135]
- Swiss National Supercomputing Center [s557]
- Swiss National Science Foundation [200021_163281]
- Gabriele Charitable Foundation
- European Union [ERC-2014-AdG-670227-VARMET]
- Swiss National Center for Computational Design and Discovery of Novel Materials MARVEL
- Commissione Europea
- Fondo Sociale Europeo
- Regione Calabria
- Italian Ministry of Education MIUR-PRIN [E61J12000210001]
- FIRB-IDEAS [RBID082ATK_002]
- Programma STAR of University of Naples Federico II [14-CSP3-C03-141]
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G-quadruplexes (G4s) are higher-order DNA structures typically present at promoter regions of genes and telomeres. Here, the G4 formation decreases the replicative DNA at each cell cycle, finally leading to apoptosis. The ability to control thismitotic clock, particularly in cancer cells, is fascinating and passes through a rational understanding of the ligand/G4 interaction. We demonstrate that an accurate description of the ligand/G4 binding mechanism is possible using an innovative free-energy method called funnel-metadynamics (FM), which we have recently developed to investigate ligand/protein interaction. Using FM simulations, we have elucidated the binding mechanism of the anticancer alkaloid berberine to the human telomeric G4 (d[AG(3)(T(2)AG(3)) (3)]), computing also the binding free-energy landscape. Two ligand binding modes have been identified as the lowest energy states. Furthermore, we have found prebinding sites, which are preparatory to reach the final binding mode. In our simulations, the ions and the water molecules have been explicitly represented and the energetic contribution of the solvent during ligand binding evaluated. Our theoretical results provide an accurate estimate of the absolute ligand/DNA binding free energy (Delta G(b)(0) = -10.3 +/- 0.5 kcal/mol) that we validated through steady-state fluorescence binding assays. The good agreement between the theoretical and experimental value demonstrates that FM is a most powerful method to investigate ligand/DNA interaction and can be a useful tool for the rational design also of G4 ligands.
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