Tailored Transition‐Metal Coordination Environments in Imidazole‐Modified DNA G‐Quadruplexes

Philip M Punt,Guido H Clever

doi:10.1002/chem.201903445

Abstract

Two types of imidazole ligands were introduced both at the end of tetramolecular and into the loop region of unimolecular DNA G‐quadruplexes. The modified oligonucleotides were shown to complex a range of different transition‐metal cations including NiII, CuII, ZnII and CoII, as indicated by UV/Vis absorption spectroscopy and ion mobility mass spectrometry. Molecular dynamics simulations were performed to obtain structural insight into the investigated systems. Variation of ligand number and position in the loop region of unimolecular sequences derived from the human telomer region (htel) allows for a controlled design of distinct coordination environments with fine‐tuned metal affinities. It is shown that CuII, which is typically square‐planar coordinated, has a higher affinity for systems offering four ligands, whereas NiII prefers G‐quadruplexes with six ligands. Likewise, the positioning of ligands in a square‐planar versus tetrahedral fashion affects binding affinities of CuII and ZnII cations, respectively. Gaining control over ligand arrangement patterns will spur the rational development of transition‐metal‐modified DNAzymes. Furthermore, this method is suited to combine different types of ligands, for example, those typically found in metalloenzymes, inside a single DNA architecture.

Highlights

Transition metals are key players in countless central processes ranging from structural stabilization over electron transport and oxygen metabolism to enzyme catalysis.[1]
The inclusion in tetramolecular G-quadruplexes offer only limited control of ligand number and arrangement (3’ and/or 5’ end),[11,12a,13] we show that unimolecular Gquadruplexes present a highly robust system to vary the position and number of incorporated ligands. We present how this approach allows us to fine-tune the coordination environment of different transition-metal cations with respect to their preferred coordination number and geometry
Considering that the number of imidazole ligands is constant in all three sequences, the changes in thermal stability can be assigned to the spatial arrangement of the ligands

Summary

Introduction

Transition metals are key players in countless central processes ranging from structural stabilization over electron transport and oxygen metabolism to enzyme catalysis.[1]. In accordance with our previously reported results for L1, the L2modified G-quadruplexes G4L2R and G4L2S were observed to complex CuII, NiII, ZnII and CoII[14] cations as indicated by strong thermal stabilization effects (Table 1; Supporting Information, Table S3) by retaining the all-parallel topology.

Results

Conclusion