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Stabilizing interactions and rational design of non-canonical G-quadruplexes

Subject Area Biological and Biomimetic Chemistry
Biophysics
Physical Chemistry of Molecules, Liquids and Interfaces, Biophysical Chemistry
Structural Biology
Term from 2018 to 2024
Project identifier Deutsche Forschungsgemeinschaft (DFG) - Project number 410497337
 
Final Report Year 2024

Final Report Abstract

Tetra-stranded G-quadruplexes (G4s) are alternative secondary nucleic acid structures that have attracted enormous interest during the last two decades. The relevance of these structures derives from their occurrence within genomic sequences and their role in the control of many physiological processes, making them attractive targets for medicinal interventions. In addition, G4s have been shown to be promising scaffolds for many technological applications, e.g., serving as DNAzymes, aptamers, or nanoswitches. A striking characteristic of G4s is their structural variability and the formation of different topologies. Clearly, the reliable prediction of a G4 fold given a particular sequence, but also the engineering of a specific G4 structure for technological applications, is crucial for making full advantage of the potential associated with G4s. Because there is still a lack in understanding internal G4 interactions, especially in case of non-regular G4 folds harboring interrupted G-columns as seen with V-shaped or snapback loops, the present project aimed at identifying critical factors as determinants of G4 folding pathways. In a first step, the impact of G nucleotide conformation was evaluated through a deliberate incorporation of G analogs with specific conformational preferences, affording novel types of G4 folds that have not been reported before. Remarkably, non-regular G4s with structurally unique V-shaped loops could be grouped in two conformationally distinct families and have been shown to even outcompete the formation of a regular G4 topology in certain cases. Realizing the importance of intervening sequences in forming different G4 topologies through their folding into different types of loops, we initially designed sequences that allowed an exclusive assessment of length- and composition-dependent internal loop interactions. These studies provided for a better molecular understanding of some well-known empirical rules. in In extending such studies, additional loop-loop or loop-overhang interactions were evaluated, showing more general patterns of tertiary interactions but also demonstrating their subtle interplay and the associated complexity of predicting a major folding pathway by sequence information alone. Finally, duplex extensions with Watson-Crick base pairing have been found to be valuable tools in enforcing a particular G4 fold. Characterizing such quadruplex-duplex hybrids in more detail, promising properties emerged for their future use. Thus, the unique quadruplex-duplex interface does not only constitute an excellent high-affinity binding site for many G4 ligands, but may also trigger conformational transitions with possible applications, e.g., as a pH-responsive switchable element.

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