On the Mechanism of Gold/NHC Compounds Binding to DNA G-Quadruplexes: Combined Metadynamics and Biophysical Methods

Darren Wragg; Andreia de Almeida; Riccardo Bonsignore; Fritz E Kühn; Stefano Leoni; Angela Casini

doi:10.1002/anie.201805727

On the Mechanism of Gold/NHC Compounds Binding to DNA G-Quadruplexes: Combined Metadynamics and Biophysical Methods

Angew Chem Int Ed Engl. 2018 Oct 26;57(44):14524-14528. doi: 10.1002/anie.201805727. Epub 2018 Jul 25.

Authors

Darren Wragg¹, Andreia de Almeida¹, Riccardo Bonsignore¹, Fritz E Kühn², Stefano Leoni¹, Angela Casini^{1

3}

Affiliations

¹ School of Chemistry, Cardiff University, Park Place, CF10 3AT, Cardiff, UK.
² Molecular Catalysis, Department of Chemistry, Catalysis Research Center, Technische Universität München, Lichtenbergstr. 4, 85747, Garching bei München, Germany.
³ Institute for Advanced Study, Technische Universität München, Lichtenbergstr. 2a, 85747, Garching bei München, Germany.

PMID: 29972613
DOI: 10.1002/anie.201805727

Abstract

The binding modes and free-energy landscape of two Au^I /N-heterocyclic carbene complexes interacting with G-quadruplexes, namely a human telomeric (hTelo) and a promoter sequence (C-KIT1), are studied here for the first time by metadynamics. The theoretical results are validated by FRET DNA melting assays and provide an accurate estimate of the absolute gold complex/DNA binding free energy. This advanced in silico approach is valuable to achieve rational drug design of selective G4 binders.

Keywords: DNA; G-quadruplexes; N-heterocyclic carbenes; anticancer; gold.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

DNA / chemistry*
Fluorescence Resonance Energy Transfer
G-Quadruplexes*
Gold / chemistry*
Molecular Structure

Substances

Gold
DNA