Modeling and NMR Data Elucidate the Structure of a G‑Quadruplex–Ligand Interaction for a Pu22T-Cyclometalated Iridium(III) System

Cyclometalated iridium(III) complexes are increasingly being developed for application in G-quadruplex (GQ) nucleic acid biosensors. We monitored the interactions of a GQ structure with an iridium(III) complex by nuclear magnetic resonance (NMR) titrations and subsequently compared the binding site inferred from NMR with binding positions modeled by molecular docking and molecular dynamics simulations. When titrated into a solution of G-quadruplex Pu22T, compound 1(PF6), [Ir(ppy)2(pizp)](PF6), where ppy is 2-phenylpyridine and pizp is 2-phenylimidazole[4,5f][1,10]phenanthroline, had the greatest impact on the hydrogen chemical shifts of G5, G8, G9, G13, and G17 residues of Pu22T, indicating end-stacking at the 5′ tetrad. In blind cross-docking studies with Autodock 4, end-stacking at the 5′ tetrad was found as the lowest energy binding position. AMBER molecular dynamics simulations resulted in a refined binding position at the 5′ tetrad with improved pi stacking. For this model system, Pu22T-1, molecular docking and molecular dynamics simulations are tools that are able to predict the experimentally determined binding position.