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

• Applicant: Professor Dr. Klaus Weisz
• 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

Because of their possible biological role, G-quadruplexes (G4s) have attracted considerable interest as novel targets for pharmaceutical interventions. Additionally, G4s have also been increasingly employed as powerful tools in various technological applications, e.g., as aptamers, sensors, or electronic switches. Their highly polymorphous nature offers excellent opportunities for their specific recognition and functional optimization. However, due to poor understanding of critical interactions that drive a G-rich sequence into a particular fold, the rational design of arbitrary quadruplex topologies and sequencebased structural predictions are restricted, especially for noncanonical G4 structures featuring broken G-columns. In continuation of an ongoing project, competitive folding to canonical and noncanonical structures will be studied through the optimization of G-tract intervening sequences to select for defined structures. Emphasis will be placed on frequently occurring non-canonical topologies with Vshaped or snapback loops. The determination of high-resolution NMR structures combined with calorimetry-derived thermodynamic stabilities is expected to give valuable insight into critical interactions that are able to enforce and stabilize corresponding G4 species. An attractive tool for guiding a fold includes quadruplex-duplex (Q-D) interfaces when formed upon structural rearrangements to the target G4. Here, binding of specific ligands at the Q-D junction, also serving as putative recognition hotspots within the genome, may additionally shift equilibria and thus be employed for inducing alternative folds. Findings are expected to promote both structure predictions and the rational design of canonical and in particular non-canonical G4 structural motifs.

• DFG Programme: Research Grants