Heteroleptic Coordination Environments in Metal-Mediated DNA G-Quadruplexes

Abstract

The presence of metal centers with often highly conserved coordination environments is crucial for roughly half of all proteins, having structural, regulatory, or enzymatic function. To understand and mimic the function of metallo-enzymes, bioinorganic chemists pursue the challenge of synthesizing model compounds with well-defined, often heteroleptic metal sites. Recently, we reported the design of tailored homoleptic coordination environments for various transition metal cations based on unimolecular DNA G-quadruplex structures, templating the regioselective positioning of imidazole ligandosides L I. Here, we expand this modular system to more complex, heteroleptic coordination environments by combining L I with a new benzoate ligandoside L B within the same oligonucleotide. The modifications still allow the correct folding of parallel tetramolecular and antiparallel unimolecular G-quadruplexes. Interestingly, the incorporation of L B results in strong destabilization expressed in lower thermal denaturation temperatures T m. While no transition metal cations could be bound by G-quadruplexes containing only L B , heteroleptic derivatives containing both L I and L B were found to complex Cu II , Ni II , and Zn II. Especially in case of Cu II we found strong stabilizations of up to T m = +34 • C. The here shown system represents an important step toward the design of more complex coordination environments inside DNA scaffolds, promising to culminate in the preparation of functional metallo-DNAzymes.

Precise Distance Measurements in DNA G‐Quadruplex Dimers and Sandwich Complexes by Pulsed Dipolar EPR Spectroscopy

“…Pyridine or imidazole donors were covalently incorporated into defined positions of G-quadruplex structures, equipping the folded strands with prearranged chelate environments suitable for binding transition metal ions such as Co 2+ , Ni 2+ , Cu 2+ , or Zn 2+ . [68][69][70][71][72] Substantial thermal stabilization of the metal ion-bound structures was observed, and the system allows for metal-induced control of its folding topology and protein binding behavior. [73] Here, we extend the use of the Cu(pyridine) 4 tetrad as a rigid spin label to detect intermolecular Cu 2+ -Cu 2+ distances in G-quadruplex dimers of different spatial dimensions.…”

“…In earlier studies, we transferred this concept from duplex DNA to G‐quadruplexes. Pyridine or imidazole donors were covalently incorporated into defined positions of G‐quadruplex structures, equipping the folded strands with prearranged chelate environments suitable for binding transition metal ions such as Co 2+ , Ni 2+ , Cu 2+ , or Zn 2+ [68–72] . Substantial thermal stabilization of the metal ion‐bound structures was observed, and the system allows for metal‐induced control of its folding topology and protein binding behavior [73] …”

“…[66,67] In earlier studies, we transferred this concept from duplex DNAt oG -quadruplexes.P yridine or imidazole donors were covalently incorporated into defined positions of G-quadruplex structures,e quipping the folded strands with prearranged chelate environments suitable for binding transition metal ions such as Co 2+ ,N i 2+ ,C u 2+ ,o rZ n 2+ . [68][69][70][71][72] Substantial thermal stabilization of the metal ion-bound structures was observed, and the system allows for metal-induced control of its folding topology and protein binding behavior. [73] Here,w ee xtend the use of the Cu(pyridine) 4 tetrad as arigid spin label to detect intermolecular Cu 2+ -Cu 2+ distances in G-quadruplex dimers of different spatial dimensions.T his approach also revealed new binding modes in related sandwich complexes with PIPER, telomestatin, and Gquartets assembled from free guanines.O ur study delivers valuable information on binding stoichiometry and key structural parameters,which are in excellent agreement with MD simulation results.…”

The Research of G–Motif Construction and Chirality in Deoxyguanosine Monophosphate Nucleotide Complexes

“…The non–B-DNA secondary structures known as G-quadruplex (G4), formed by alternative GG Hoogsteen mismatches at physiological temperature and potassium concentration, found in oncogene promoters and telomeres are often used as antitumor and antibacterial targets ( Musumeci et al, 2016 ; Hansel-Hertsch et al, 2017 ; Hansel-Hertsch et al, 2018 ; Punt et al, 2020 ). The appealing possibility to treat cancers without impairing normal cells stimulated the synthesis of large libraries of putative selective G-quadruplex targeted ligands.…”

Präzise Abstandsmessungen in DNA‐G‐Quadruplex‐Dimeren und Sandwichkomplexen über gepulste dipolare EPR‐Spektroskopie

“…[66,67] In früheren Studien übertrugen wir dieses Konzept bereits von Duplex-DNAa uf G-Quadruplexe.D urch den kovalenten Einbau von Pyridinoder Imidazoldonoren an bestimmten Stellen in G-Quadruplexstrukturen wurden die gefalteten Stränge mit vororientierten Chelatumgebungen ausgestattet, die sich zur Bindung von Metallkationen wie Co 2+ ,N i 2+ ,C u 2+ oder Zn 2+ eigneten. [68][69][70][71][72] Es wurde eine beträchtliche thermische Stabilisierung der metallgebundenen Strukturen beobachtet. Ferner ermçglicht das System die metallinduzierte Kontrolle über seine Faltungstopologie und erlaubt es,d ie Bindung von Proteinen zu kontrollieren.…”