Oligodeoxyribonucleotide length and sequence effects on intramolecular and intermolecular G-quartet formation

Area of Science:

• Biochemistry
• Molecular Biology
• Medicinal Chemistry

Background:

• Guanine-rich oligonucleotides (G-rich oligos) show promise as nucleic acid drugs, acting as aptamers or forming triplex structures.
• G-rich oligos exhibit significant structural polymorphism under physiological conditions, impacting their functional capabilities.
• Understanding the relationship between oligo sequence and structure is crucial for developing effective nucleic acid therapeutics.

Purpose of the Study:

• To investigate how intrinsic oligo parameters influence the self-association of G-rich oligos through G-quartet formation.
• To elucidate the structural preferences of G-rich oligos based on the number and arrangement of guanine clusters.
• To determine the effect of T-rich extensions on G-rich oligo multimerization.

Main Methods:

• Nondenaturing gel electrophoresis was employed to analyze the self-association of G-rich oligos.
• A series of G-rich oligos derived from the sequence 5'-TGGGTGGGGTGGGGTGGGT were synthesized and studied.
• Oligonucleotide structures were assessed based on their ability to form G-quartets and self-associate.

Main Results:

• Oligos with four clusters of three or more contiguous Gs predominantly formed intramolecular structures, with no observed intermolecular association.
• Intermolecular dimerization was favored when an oligo contained only two G clusters.
• T-rich extensions on the oligos promoted the formation of higher-order multimers.

Conclusions:

• The number and arrangement of guanine clusters in G-rich oligos critically control their self-association behavior (intramolecular vs. intermolecular).
• T-rich sequences can induce multimerization, leading to complex higher-order structures.
• These findings provide insights into the structural determinants of G-rich oligos, essential for designing nucleic acid-based drugs.