Locked nucleic acid building blocks as versatile tools for advanced G-quadruplex design

Area of Science:

• Biochemistry
• Structural Biology
• Nucleic Acid Chemistry

Background:

• G-quadruplexes are four-stranded nucleic acid structures with diverse biological roles.
• Modifications like locked nucleic acid (LNA) can alter G-quadruplex stability and structure.
• Understanding these modifications is key to designing novel nucleic acid-based applications.

Purpose of the Study:

• To investigate the structural impact of LNA and 2'-F-riboguanosine modifications on hybrid G-quadruplexes.
• To determine the stabilizing effects of LNA in different structural contexts.
• To explore the potential of LNA for designing complex G-quadruplex architectures.

Main Methods:

• Synthesis of modified hybrid G-quadruplexes incorporating LNA and 2'-F-riboguanosine.
• Structural analysis using techniques to determine G-quadruplex conformation.
• Comparative stability studies of modified versus unmodified G-quadruplexes.

Main Results:

• LNA substitution in the central tetrad induced structural rearrangements to V-loop or antiparallel forms.
• The specific outcome of LNA modification depended on adjacent modifications.
• LNA demonstrated superior stabilization compared to other G-surrogates in distinct structural contexts.
• LNA modification at the V-loop 3'-end favored a conventional V-loop structure over an alternative.

Conclusions:

• LNA is a potent tool for stabilizing and directing the formation of complex G-quadruplex structures.
• LNA modifications offer a versatile strategy for designing diverse G-quadruplex topologies beyond parallel structures.
• These findings have implications for the development of G-quadruplex-based therapeutics and nanomaterials.