Controlling G-quadruplex formation via lipid modification of oligonucleotide sequences

Area of Science:

• Supramolecular Chemistry
• Nucleic Acid Nanotechnology
• Biophysical Chemistry

Background:

• G-quadruplexes (G4) are four-stranded nucleic acid structures with significant potential as supramolecular scaffolds.
• Controlling the formation and conformation of G4 structures is crucial for their application in nanotechnology and medicine.
• Oligonucleotide folding can lead to various non-specific structures, limiting G4 applications.

Purpose of the Study:

• To investigate the effect of lipid modification on G-quadruplex (G4) prone oligonucleotide sequences.
• To determine if lipid modification can enhance the formation of specific G4 architectures, particularly tetramolecular parallel G4s.
• To assess the conformational control achieved through lipid modification compared to unmodified sequences.

Main Methods:

• Synthesis of lipid-modified G4-prone oligonucleotide sequences.
• Structural analysis using biophysical techniques (e.g., NMR, CD spectroscopy) to characterize G4 formation.
• Comparative analysis of folding pathways and resulting structures in lipid-modified versus unmodified oligonucleotides.

Main Results:

• Lipid modification significantly increases the probability of forming tetramolecular parallel G4 structures.
• The modified G4s exhibit enhanced conformational stability and specificity.
• Lipid modification effectively suppresses the formation of other non-specific oligomers and folds.

Conclusions:

• Lipid modification is a powerful strategy for directing the self-assembly of G-quadruplex (G4) oligonucleotides into desired architectures.
• This approach provides unprecedented conformational control over G4 formation, enabling the design of specific supramolecular structures.
• The findings open new avenues for utilizing lipid-modified G4s in nanotechnology, drug delivery, and diagnostics.