Unexpected Position-Dependent Effects of Ribose G-Quartets in G-Quadruplexes

Area of Science:

• Structural biology
• Biochemistry
• Nucleic acid chemistry

Background:

• G-quadruplexes are nucleic acid structures with diverse biological roles.
• Understanding modifications like ribose substitutions is key to their function.
• Previous assumptions about RNA stabilizing G-quadruplexes need re-evaluation.

Purpose of the Study:

• To investigate the impact of ribose G-quartets on G-quadruplex stability and structure.
• To determine the position-dependent effects of ribose substitutions.
• To explore novel G-quadruplex topologies induced by ribose incorporation.

Main Methods:

• Synthesis of DNA G-quadruplexes with varying numbers of ribose G-quartet substitutions.
• Thermal denaturation experiments to assess G-quadruplex stability.
• Two-dimensional Nuclear Magnetic Resonance (2D NMR) spectroscopy for structural analysis.

Main Results:

• Ribose G-quartets exhibit position-dependent and cumulative effects on G-quadruplex stability.
• Unexpected destabilization was observed with 5 étaire-end ribose G-quartets.
• Hydration was not the primary factor in chimeric G-quadruplex stability.
• Central ribose G-quartets promoted new tetramolecular topologies with distinct CD signals.
• NMR revealed syn conformation of Gs in the 5 étaire-most G-quartet of a chimeric structure.

Conclusions:

• The position of ribose residues critically tunes G-quadruplex properties.
• Ribose G-quartets can destabilize G-quadruplexes, contrary to general expectations.
• This study reveals new insights into RNA/DNA chimeric G-quadruplexes and their structural plasticity.