C3 - Resolving the dynamics of G-Quadruplexes using biochemistry, infrared spectroscopy, and molecular dynamics simulation
Nucleic acids (NA) can fold into a variety of different structures. It is postulated that in living cells, these structures are highly dynamic. Changes in NA-structure formation can be triggered by external stimuli, such as protein binding, metabolic changes as well as exogenous threats e.g., UV light. In recent years, particular attention was paid to the guanine (G)-rich NA-structures, called G-quadruplexes (G4), due to their therapeutic potential. G4-quadruplexes are involved in replication, gene expression changes of oncogenes, induced apoptosis, and reduced telomerase activity. Thus, enforced G4-formation may potentially be used as a novel anti-tumor strategy. The long-term goal of this project is to monitor the structural dynamics during G4-folding and unfolding as well as G4-protein interactions using laser-based infrared (IR) spectroscopic tools. Knowledge of such dynamics and their interrelation with the NA sequence is needed for comprehensively understanding their biological function and may assist in the future in the rational design of G4-based therapeutics.
Figure 1: A) Schematic representation of a four-stranded, parallel G-quadruplex containing five G4 layers. B) The G4 structural element. C), D) NMR demonstrates that this RNA sequence folds into a thermostable and denaturant-resistant G-quadruplex. E) FTIR-spectrum of the G4 from the 5' AG5CC 3' fragment in D2O (red) and theoretical spectra of the various isotopologues (from top to bottom: all NH2 and NH-groups fully deuterated, all NH2 and NHout groups deuterated, all NH2 groups deuterated, fully hydrogenated). F) DFT-optimized structure of a G4-dimer bound to a central K+-cation.